experience working with him and under his guidance which inspires and motivates me a lot towards the scientific research.

I would like to thank Prof. Sebastien Ulrich from Université de Montpellier, Prof.

Ghislaine Vantomme from Eindhoven University of Technology, Prof. Jean-Claude Chambron from University of Strasbourg for examination of my work.

Besides, I would also like to express my thank to Prof. Jack Harrowfield for his insightful discussions and suggestions on my research work as well as the carefully correcting my manuscripts both Chemistry and English. I would also like to Dr. Artem Osypenko for his valuable suggestions on my projects as well as correction of my thesis. I must thank the others who helped correcting my thesis, Dr. Youssef Atoini, Aline Chevalier, Dr. Jean-louis Schmidt and Prof. Andrian-Mihail Stadler.

I would like to thank Dr. Jean-Louis Schmitt and Cyril Athenaeums for their help in the laboratory and measurement of nmr. More thanks should give to Dr. Artem Osypenko and Dr.

Jean-Francois Ayme, who have stayed in the same lab 515 with me for 4 years and gave me many suggestions and help on the research. I would like to thank all the current and former lab members in Prof. Lehn's group, particularly Dr. Ruirui Gu and Dr. Chunshuang Liang who has helped me a lot when I first arrived in Strasbourg in late September 2016, and the others: Sirinan, Jan, Martin, Sebastien, Guangwen, Liyuan, Antonio, Chanon, Wissuta, Annia for her help of preparing the documents before I came here, Jacline for her kindness, Stanislav, Bohdan, Michal, Kumar, Chenna, Juan, Zhaozheng, Chengyi, and most of all, Aline Chevalier, who has stayed with me in the lab for three years and always support me in many ways and cheering me up during the hard time.

I am thankful to my former master supervisor Prof. Yu Fang for his support. He was and remains a good scientist and mentor. He inspired me to go to pursue a career in research. His enthusiasm, persistence and love for research is contagious. undergo changes in constitution by component recombination through the implementation of reversible covalent reactions and non-covalent linkages. Therefore, many efforts were devoted to facilitation of dynamic covalent reactions (DCR) as well as to construction of dynamic covalent libraries (DCLs) for the applications in catalysis, materials, and biology.

Here we illustrated the study of DCC in several aspects: a) kinetics and facilitation of C=N formation in organic phase; b) time-dependent switching of DCLs in the absence and in the presence of metal salts; c) increasing of imine formation yield in aqueous phase.

As a result of the widely application of DCRs, it is of great importance to develop effective methods to accelerate the corresponding kinetics. We have investigated the formation of imines and hydrazones from their components both in the absence and presence of AgOTf or Zn(OTf)2.

Very large acceleration by factors up to about 10,000 was observed for the formation of the imine complex in presence of Zn(OTf)2 compared to the formation of the imine itself.

Formation of the complexed hydrazone ligand was also moderately accelerated by a factor of 8-14 on addition of Zn(OTf)2 or AgOTf and notably, organocatalysis of hydrazone formation by a similar factor was induced by the auxiliary amine p-anisidine. Through the synergistic operation of both Zn(OTf)2 and the p-anisidine, the formation of the zinc complex of the hydrazone ligand was enhanced by a factor of about 630 in comparison to the formation of the hydrazone itself in absence of Zn(OTf)2. A similar fast reaction is obtained in a three-catalyst setup, combining the two metal salts and the auxiliary amine. Thus, the metal salts and amine together display a strongly synergistic facilitation on the formation of the Zn(II) hydrazone complex.

Combining both metallo-and organo-catalysis, this mode of synergistic effect points to a powerful strategy of co-catalysis of bond-formation in DCC through synergistic interconnected chemical transformations and exemplifies dynamic systems that generate kinetically faster and thermodynamically simpler outputs from mixtures of higher complexity.

Abstract x

The dynamic covalent reactions can be utilized to build up CDLs which adapt to external effectors resulting in component selection through the change in constitution of the DCLs. We have explored the behavior of dynamic covalent libraries (DCLs) of four constituents generated by the reversible formation of C=N bonds between four components, both in the absence and in the presence of metal cations. The [2 × 2] networks associated to these DCLs undergo timedependent changes with the variation in the distributions of the constituents. The kinetic network established at the initial generation of the constituents progressively changes to the final thermodynamic one, thus undergoing a switching from a kinetic to the thermodynamic state, involving an orthogonal switching from one diagonal to the other diagonal of the square [2 × 2] network. The set of DCL constituents could be switched from the kinetic products (imines) to thermodynamic products (oxime or acylhydrazone) based on the reactivities of the components and the thermodynamic stabilities of the constituents without addition of any other external effectors, i.e. solely on the basis of the intrinsic properties of the self-contained system. Such processes were achieved for purely organic DCLs/DCNs as well as for inorganic ones containing two metal cations, e.g. silver (I) and zinc (II). In the latter inorganic cases, network switching involved changing from the silver(I) complex of an imine (kinetic product) to the zinc complex of a hydrazone (thermodynamic product). Therefore, the DCLs and the associated DCNs could be switched for either organic or inorganic systems. The results also bear relationship to the behavior of out-of-equilibrium systems opening towards kinetic behavior in adaptive chemistry. [START_REF] Ma | Biomedical Applications of Supramolecular Systems Based on Host-Guest Interactions[END_REF] Imine formation has been extensively studied in mechanism and kinetics, there remains a need for an effective method to increase the yield of imine formation in aqueous phase. We have investigated imine formation from a variety of aldehydes with lysine derivatives to screen the best aldehyde for the highest yield of imine in aqueous phase. Pyridoxal phosphate was first chosen due to its coenzyme role in a variety of enzymatic reactions. The para-N could activate the aldehyde and the ortho-OH could stabilize the generated imine to drive the equilibrium of imine formation. pH titration experiment indicated that the imine forms a higher yield in the pH around 10 to 11. In addition, one also notes that pyridoxal phosphate the most prospective one with 65% imine (pH=11) among all the tested aldehydes. The reaction of PLP with monolysine and polylysine provided a model for histone modification since histones are abundant in lysines. This result indicated the possibility of imine formation for dynamic gene regulation. This project is still ongoing, and more experiments still need to be done. Une accélération très importante (par des facteurs allant jusqu'à 10 4 ) a été observée pour la formation du complexe d'imine en présence de Zn(OTf)2 en comparaison avec la formation de l'imine seul en absence de sel métallique. La formation d'hydrazone compléxée a également été modérément accélérée par un facteur de 8 à 14 lors de l'addition de Zn(OTf)2 ou de AgOTf. En conclusion, dans cette thèse, nous avons illustré plusieurs aspects de la formation et de l'échange de liaisons C=N dans la CDC : catalyse, cinétique et thermodynamique, comportement de commutation cinétique et états hors-équilibre.

ABBREVIATIONS AND SYMBOLS

Pour résumer le présent travail, nous avons élargi nos connaissances et notre compréhension de la CDC d'imines, en particulier du point de vue cinétique, ce qui a longtemps été sous-étudié. La compréhension de l'influence des effets structurels sur le comportement cinétique et thermodynamique ouvre la voie à l'établissement de systèmes complexes pour générer une production plus rapide et plus simple en chimie adaptative. De plus, ces études ont indiqué des applications potentielles en biologie.

CHAPTER I. GENERAL BIBLIOGRAPY 1. FROM SUPRAMOLECULAR CHEMISTRY TO CONSTITUTIONAL DYNAMIC CHEMISTRY

Supramolecular chemistry has undergone a booming development during the last decades with its wide application in catalysis, sensing, materials, and others. It is defined by J.-M. Lehn as "chemistry beyond the molecule" where supramolecular entities are built by linking the molecular components through intermolecular forces. This research field was initially established in the last century based upon the exploitation of non-covalent forces. An important step occurred in the 1960s, when Charles Pedersen 1,2 successfully synthesized macrocyclic, "crown" ethers. The real burst came in 1987 when the Nobel Prize for chemistry was awarded to three pioneers, C. J. Pedersen, 1,2 D. J. Cram [3][4][5] and J.-M. Lehn 6,7 for their development and use of macro(poly)cyclic molecules with structure-specific interactions of high selectivity. [2][3][4][5][START_REF] Dietrich | Diaza-Polyoxa-Macrocycles et Macrobicycles[END_REF][7] Such molecules and their very numerous derivatives were the focus of the rapid development of "host-guest" chemistry, where their interactions with both organic and inorganic species led to the formation of complexes in which the macrocycle was considered the "host" (Figure 3). [START_REF] Cram | International Edition in English[END_REF] They can bind specifically with the guests inventing the concept of "molecular recognition". [START_REF] Lehn | Supramolecular Chemistry-Scope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture)[END_REF] Crown ethers and cryptands can form complexes with cations such as such as K + and NH4 + .

Cavitands can encapsulate small organic molecule into its inner cavity. Therefore, this kind of supramolecular interactions has been widely exploited in specific molecular sensing, drug delivery and extraction of hazardous chemical guests. 10 because of the lability and weak strength energy of most non-covalent interactions such as van de Waals forces, hydrogen bonding, and metal coordination. This dynamic feature permits supramolecular species to undergo reversibly association and dissociation from their molecular components. The main types of non-covalent interactions are illustrated in Table 1. Many complex architectures held by non-covalent interactions were developed, thus allowing for the self-organization with selection. The supramolecular systems thus can adapt their structures and constitution to the external effectors.

Such an example is the generation of the circular helicates of different sizes in the presence of anion from the work of Hasenknopf and Lehn (Figure 4). They demonstrated the role of counter anions as templates to guide the outcome of the self-organization of the DCL of circular helicates. [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] By mixing n equivalent of tris-bipyridine and Fe(II), they displayed the selective generation of either penta-or hexanuclear architectures depending on the different anions. The addition of FeCl2 generated the pentanuclear circular hellicate [5]cH, while the addition of FeSO4 induced the assembly of the hexanuclear [6]cH. Hence, the Fe(II) and the tris-bipy ligands were considered to generate the potential members of the virtual combinatorial library. Addition of the anions either chloride or sulfate induced the selective formation of specific polynuclear architectures. These results indicated that the virtual combinatorial library of supramolecular mixtures can adapt their structures and constitution to the effectors present. The self-assembly of circular helicates from the ligands and the Fe(II) ions in the presence of different anions (chloride or sulfate anions). [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] Metal ions were one kind of important effectors to induce the formation of many supramolecular architectures [START_REF] Kramer | Self-recognition in Helicate Self-assembly: Spontaneous Formation of Helical Metal Complexes from Mixtures of Ligands and Metal Ions[END_REF][START_REF] Brady | Thermodynamically-Controlled Cyclisation and Interconversion of Oligocholates: Metal Ion Templated "living" Macrolactonisation[END_REF][START_REF] Stadler | Supramolecular Reactions of Metallo-architectures: Ag2-Double-Helicate/Zn4-Grid, Pb4-Grid/Zn4-Grid Interconversions, And Ag2-Double-Helicate Fusion[END_REF][START_REF] Hsu | Self-Sorting through Dynamic Covalent Chemistry[END_REF][START_REF] Black | Catenation and Encapsulation Induce Distinct Reconstitutions within a Dynamic Library of Mixed-Ligand Zn4L6 Cages[END_REF][START_REF] Saha | Degree of Molecular Self-Sorting in Multicomponent Systems[END_REF][START_REF] Ji | Kinetically Controlled Phenomena in Dynamic Combinatorial Libraries[END_REF][21][START_REF] Mahata | From an Eight-Component Self-Sorting Algorithm to a Trisheterometallic Scalene Triangle[END_REF] such as two-dimensional (2-D) polygons and threedimensional (3-D) cages, [START_REF] Addicott | Self-Recognition in the Coordination Driven Self-Assembly of 2-D Polygons[END_REF][START_REF] Zheng | Multicomponent Supramolecular Systems: Self-Organization in Coordination-Driven Self-Assembly[END_REF][START_REF] Sepehrpour | Fe-Pt Twisted Heterometallic Bicyclic Supramolecules via Multicomponent Self-Assembly[END_REF][START_REF] Zhou | Understanding the Effects of Coordination and Self-Assembly on an Emissive Phenothiazine[END_REF] rotaxane, [START_REF] Jiang | Integrative Self-Sorting: Construction of a Cascade-Stoppered Hetero[3]Rotaxane[END_REF] supramolecular trapezoid, [START_REF] Mahata | From an Eight-Component Self-Sorting Algorithm to a Trisheterometallic Scalene Triangle[END_REF][START_REF] Mahata | From 2-Fold Completive to Integrative Self-Sorting: A Five-Component Supramolecular Trapezoid[END_REF][START_REF] Saha | From 3-Fold Completive Self-Sorting of a Nine-Component Library to a Seven-Component Scalene Quadrilateral[END_REF][START_REF] Saha | A Six-Component Metallosupramolecular Pentagon via Self-Sorting[END_REF][START_REF] Gaikwad | Five-Component Trigonal Nanoprism with Six Dynamic Corners[END_REF] and more complexed supramolecular structures such as circular helicates and molecular knots. [32][START_REF] Campbell | A Simple and Highly Effective Ligand System for the Copper I-Mediated Assembly of Rotaxanes[END_REF][START_REF] Ayme | A Synthetic Molecular Pentafoil Knot[END_REF] Lehn and co-workers reported many works on the self-sorting of supramolecular architectures based on metal complexes. [START_REF] Kramer | Self-recognition in Helicate Self-assembly: Spontaneous Formation of Helical Metal Complexes from Mixtures of Ligands and Metal Ions[END_REF][START_REF] Baxter | Multicomponent Self-Assembly: Spontaneous Formation of a Cylindrical Complex from Five Ligands and Six Metal Ions[END_REF][START_REF] Chow | Neutral Dynamic Metallosupramolecular Polymers Displaying Transformation of Mechanical and Optical Properties on Constitutional Exchange[END_REF][START_REF] Fujii | Structural and Functional Evolution of a Library of Constitutional Dynamic Polymers Driven by Alkali Metal Ion Recognition[END_REF][START_REF] Ulrich | Reversible Switching between Macrocyclic and Polymeric States by Morphological Control in a Constitutional Dynamic System[END_REF][39][START_REF] Ulrich | Reversible Constitutional Switching between Macrocycles and Polymers Induced by Shape Change in a Dynamic Covalent System[END_REF] For example, they investigated the generation of two helicates from a mixture of two types of tris-bipyridine ligands in the presence of two metal ions Cu(I) and Ni (II). With the bipyridine connected by ethylene bridges, penta-and hexanuclear architectures were obtained depending on the anion. With the linker of the bipyridine as oxypropylene, it formed a tetranuclear circular helicate. Through the selforganization of the constituents (tris-bipyridine ligand connected by ethylene bridges) with the two metal ions, only two structures were obtained -the double helicate incorporating copper and the triple helicate incorporating nickel (Figure 5). [START_REF] Kramer | Self-Recognition in Helicate Self-Assembly: Spontaneous Formation of Helical Metal Complexes from Mixtures of Ligands and Metal Ions[END_REF] These results implied that the systems composed of mixtures of components could selectively generate well defined architectures through self-organization by adding metal ions. The adaptation of the supramolecular systems has prompted chemists to consider importing this dynamic feature into molecular chemistry. Accordingly, it required shifting from "static" to "dynamic" covalent bonds to endow molecules with the ability to undergo dynamic exchange and recombination processes passing through the reversible formation and breaking of covalent bonds. This provides a new perspective of considering organic molecules as labile entities, in strong contrast to the conventional view. Many reversible reactions, [START_REF] Jin | Recent Advances in Dynamic Covalent Chemistry[END_REF] for example, imine formation, [START_REF] Rowan | Dynamic Covalent Chemistry[END_REF] disulfide exchange, [START_REF] Nagy | Kinetics and Mechanisms of Thiol-Disulfide Exchange Covering Direct Substitution and Thiol Oxidation-Mediated Pathways[END_REF] Diels-Alder reactions, [START_REF] Whiting | What Makes a Neutral Imino Dieneophile Undergo a Thermal, Non-Catalysed, Diels-Alder Reaction?[END_REF] provide instances where covalent chemistry can also be dynamic, with the molecular bond formed and broken rapidly under certain conditions. Thus, the discovery of these dynamic reactions has led to the emergence of dynamic covalent chemistry (DCvC). [START_REF] Belowich | Dynamic Imine Chemistry[END_REF][START_REF] Black | Disulfide Exchange: Exposing Supramolecular Reactivity through Dynamic Covalent Chemistry[END_REF][START_REF] Herrmann | Dynamic Combinatorial/Covalent Chemistry: A Tool to Read, Generate and Modulate the Bioactivity of Compounds and Compound Mixtures[END_REF][START_REF] Meguellati | Reversible Covalent Chemistries Compatible with the Principles of Constitutional Dynamic Chemistry: New Reactions to Create More Diversity[END_REF][START_REF] Jin | Recent Advances in Dynamic Covalent Chemistry[END_REF][START_REF] Sadownik | Dynamic Covalent Chemistry in Aid of Peptide Self-Assembly[END_REF][52][START_REF] Gasparini | Dynamic Covalent Chemistry[END_REF][START_REF] Lehn | From Supramolecular Chemistry towards Constitutional Dynamic Chemistry and Adaptive Chemistry[END_REF] Therefore, this constitutional change of the components can exist both at the supramolecular and molecular levels and underlies the field of Constitutional Dynamic Chemistry (CDC). [START_REF] Jin | Recent Advances in Dynamic Covalent Chemistry[END_REF][START_REF] Lehn | Dynamic Combinatorial Chemistry and Virtual Combinatorial Libraries[END_REF][START_REF] Barboiu | Constitutional Dynamic Chemistry[END_REF][START_REF] Huc | Virtual Combinatorial Libraries: Dynamic Generation of Molecular and Supramolecular Diversity by Self-Assembly[END_REF][START_REF] Lehn | Perspectives in Chemistry -Aspects of Adaptive Chemistry and Materials[END_REF][START_REF] Corbett | Dynamic Combinatorial Chemistry[END_REF][START_REF] Hunt | Dynamic Combinatorial Libraries: New Opportunities in Systems Chemistry[END_REF][START_REF] Schaufelberger | Principles of Dynamic Covalent Chemistry[END_REF] CDC gives rise to both the formation and dynamic features of these molecular and supramolecular entities resulting from condensation of the building blocks (components) through reversible covalent and non-covalent interactions. In both cases, there is always the recombination of the building blocks, which was also defined as Dynamic

Combinatorial Chemistry (DCC) by Sanders. [START_REF] Corbett | Dynamic Combinatorial Chemistry[END_REF] Therefore, the field of DCvC and DNCC resulted in DCC from the combinatorial point of view and constitutional dynamic chemistry from the compositional point of view (Figure 6). [START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF] Upon action of chemical effectors or physical stimuli, CDC allows a system to respond to such event by changing the constitution of the system through component exchange and reorganization, thus generating selection and amplification of one of the products (constituents) within the system. [START_REF] Giuseppone | Protonic and Temperature Modulation of Constituent Expression by Component Selection in a Dynamic Combinatorial Library of Imines[END_REF][START_REF] Hafezi | Adaptation of Dynamic Covalent Systems of Imine Constituents to Medium Change by Component Redistribution under Reversible Phase Separation[END_REF][START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Men | Multiple Adaptation of Constitutional Dynamic Networks and Information Storage in Constitutional Distributions of Acylhydrazones[END_REF][START_REF] Ayme | Self-Sorting of Two Imine-Based Metal Complexes: Balancing Kinetics and Thermodynamics in Constitu-tional Dynamic Networks[END_REF] Figure 6. Constitutional dynamic chemistry (CDC) at both molecular and supramolecular level, involving dynamic covalent and supramolecular chemistry for both reversible covalent and non-covalent interactions. [START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF] As noted above, dynamic combinatorial chemistry was first developed by Sanders through macrolactonization [START_REF] Brady | Thermodynamically-Controlled Cyclisation and Interconversion of Oligocholates: Metal Ion Templated "living" Macrolactonisation[END_REF] and by Lehn through "virtual combinatorial libraries" as well as "dynamic combinatorial libraries (DCLs)" in making the helicates through the self-organization from the mixtures [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF][START_REF] Hasenknopf | Self-Assembly of a Circular Double Helieate[END_REF] and protein-directed DCC. [START_REF] Huc | Virtual Combinatorial Libraries: Dynamic Generation of Molecular and Supramolecular Diversity by Self-Assembly[END_REF] The process to generate dynamic diversity resulted in the so-called dynamic combinatorial libraries (DCLs). The following parameters used to describe DCLs are summarized below: [START_REF] Schaufelberger | Principles of Dynamic Covalent Chemistry[END_REF] a) The conversion, that is, the total amount of constituents generated with respect to the free components.

b) The composition, that is, the distribution or relative amounts of the different constituents that also represents the selectivity of the system.

c) The product of conversion and selectivity may be considered as defining the expression of a given constituent.

The most important feature of DCLs lies in the self-assembly under thermodynamic control. The differences in the thermodynamic stabilities of the constituents (the relative Gibbs free energy) determine the conversion of the components into the constituents, resulting in the final distribution of the DCL. Such a constitutional dynamic library (CDL) or DCL [START_REF] Huc | Virtual Combinatorial Libraries: Dynamic Generation of Molecular and Supramolecular Diversity by Self-Assembly[END_REF][START_REF] Li | Dynamic Combinatorial Libraries: From Exploring Molecular Recognition to Systems Chemistry[END_REF][START_REF] Cougnon | Evolution of Dynamic Combinatorial Chemistry[END_REF] could be illustrated in Figure 7. First, the components should be able to form a collection of constituents to generate a CDL via dynamic covalent reactions. Then, the self-organization with selection will occur on addition of effectors by the specific binding with the fittest constituent (e.g. best binder). 73 The development of the CDC attracted many interests of scientists to explore the use of dynamic covalent bonds to establish DCLs.

A very early example of using transesterification to build up DCLs from macrocycles of esters. Sanders and co-workers developed the DCLs of base-catalyzed transesterification (Figure 8). They prepared a series of cholate building blocks. By removal of the methanol from the mixture, the transesterification occurred and led to the formation of macrocycles from the cholic acid under thermodynamic control. They also demonstrated the template effect of metal ions on the generated macrocycles to select the best binder. The reaction was rather slow to reach the equilibrium and only few catalysts were sufficiently active. Afterwards, they developed DCLs of hydrazone formation, further disulfide exchange and studied many DCLs from the exchange of disulfide which proceeded controllable and reversible under mild conditions. [START_REF] Otto | Dynamic Combinatorial Libraries of Macrocyclic Disulfides in Water[END_REF][START_REF] Leclaire | Expanding Diversity in Dynamic Combinatorial Libraries: Simultaneous Exchange of Disulfide and Thioester Linkages[END_REF][START_REF] Corbett | What Are the Limits to the Size of Effective Dynamic Combinatorial Libraries?[END_REF][START_REF] Beeren | History and Principles of Dynamic Combinatorial Chemistry[END_REF][START_REF] Cousins | Dynamic Combinatorial Libraries of Pseudo-Peptide Hydrazone Macrocycles[END_REF][START_REF] Simpson | Dynamic Combinatorial Chemistry with Hydrazones: Libraries Incorporating Heterocyclic and Steroidal Motifs[END_REF] Figure 8. An equilibrium of the dynamic combinatorial library of cyclic steroid oligomers generated from the reversible transesterification.

Lehn and co-workers have also contributed a lot to the development of DCLs. They firstly demonstrated the construction of the DCLs of imines from the components through imine formation (Figure 9). Due to the similar structure of one imine to the known inhibitor of carbonic anhydrase, it was found to be selectively amplified from all the possible imine constituents in the DCL on addition of carbonic anhydrase. This work applied the imine constituents into DCLs and indicated the feasibility of imine chemistry for the construction of DCLs due to its fast formation.

ADAPTATION IN CONSTITUTIONAL DYNAMIC CHEMISTRY

As mentioned above, CDLs or DCLs are derived from the building blocks which can give rise to multiple library members connected with multiple equilibria through reversible transformations, thus generating diversity. The dynamic transformations involve formation of library members from building blocks, exchange reactions between the library members, and isomerization reactions either covalent or non-covalent, even conformational, if the generated library members are distinguishable from each other. Traditional static chemistry (irreversible) is intended to prepare pure compounds rather than mixtures. The addition of external effectors will lead to the redistribution of the composition of the chemical entities within the system due to the dynamic features of the DCLs. This adaptation behavior of DCLs through the selection and amplification of components leads to the emergence of the higher level of functions such as signal generation, information storage and processing and many other functions. DCL generated from four components on addition of two different effectors. [START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Ayme | Chapter One -From Coordination Chemistry to Adaptive Chemistry[END_REF] The effectors that induce the adaptation of DCLs means everything that is not within the DCL but can still affect the composition of the DCL by shifting the equilibrium, such as physical stimuli (light, [START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Ingerman | Photoswitchable Dynamic Combinatorial Libraries: Coupling Azobenzene Photoisomerization with Hydrazone Exchange[END_REF][START_REF] Vantomme | A Light-Induced Reversible Phase Separation and Its Coupling to a Dynamic Library of Imines[END_REF][START_REF] Herder | The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool To Shift Reaction Networks Out-of-Equilibrium Using Light Energy[END_REF] electric field, [START_REF] Herrmann | Electric-Field Triggered Controlled Release of Bioactive Volatiles from Imine-Based Liquid Crystalline Phases[END_REF][START_REF] Giuseppone | Electric-Field Modulation of Component Exchange in Constitutional Dynamic Liquid Crystals[END_REF] pressure, 86 temperature, [START_REF] Giuseppone | Protonic and Temperature Modulation of Constituent Expression by Component Selection in a Dynamic Combinatorial Library of Imines[END_REF][START_REF] Niu | Temperature and pH Dual-Responsive Supramolecular Polymer Hydrogels Hybridized with Functional Inorganic Nanoparticles[END_REF] precipitation 89 and other purification methods [START_REF] Meguellati | Reversible Covalent Chemistries Compatible with the Principles of Constitutional Dynamic Chemistry: New Reactions to Create More Diversity[END_REF][START_REF] Lirag | Oxidative Kinetic Self-Sorting of a Dynamic Imine Library[END_REF][START_REF] Hsu | Adsorption-Driven Self-Sorting of Dynamic Imine Libraries[END_REF][START_REF] Ji | Kinetically Controlled Phenomena in Dynamic Combinatorial Libraries[END_REF][START_REF] Ayme | Simultaneous Generation of a [2 × 2] Grid-Like Complex and a Linear Double Helicate: A Three-Level Self-Sorting Process[END_REF] or chemical effectors (metal ions, 39,[START_REF] Ulrich | Reversible Constitutional Switching between Macrocycles and Polymers Induced by Shape Change in a Dynamic Covalent System[END_REF][START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF][START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Men | Multiple Adaptation of Constitutional Dynamic Networks and Information Storage in Constitutional Distributions of Acylhydrazones[END_REF][START_REF] Ayme | Simultaneous Generation of a [2 × 2] Grid-Like Complex and a Linear Double Helicate: A Three-Level Self-Sorting Process[END_REF][START_REF] Ayme | Self-Sorting of Two Imine-Based Metal Complexes: Balancing Kinetics and Thermodynamics in Constitutional Dynamic Networks[END_REF][START_REF] He | Time-Dependent Switching of Constitutional Dynamic Libraries and Networks from Kinetic to Thermodynamic Distributions[END_REF][START_REF] Ulrich | Adaptation and Optical Signal Generation in a Constitutional Dynamic Network[END_REF][START_REF] Giuseppone | Generation of Dynamic Constitutional Diversity and Driven Evolution in Helical Molecular Strands under Lewis Acid Catalyzed Component Exchange[END_REF][START_REF] Men | Higher Order Constitutional Dynamic Networks[END_REF][START_REF] Ayme | Triple Self-Sorting in Constitutional Dynamic Networks: Parallel Generation of Imine-Based CuI, FeII, and ZnII Complexes[END_REF] the proton, [START_REF] Giuseppone | Protonic and Temperature Modulation of Constituent Expression by Component Selection in a Dynamic Combinatorial Library of Imines[END_REF][100][101][102] active molecules). The specific examples of adaptation of DCLs to different effectors are illustrated selectively in the following in details.

Constitutional dynamic libraries (CDLs

Adaptation to light

Light was one of the physical effectors to be employed in DCLs to achieve the adaptation. [START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Men | Multiple Adaptation of Constitutional Dynamic Networks and Information Storage in Constitutional Distributions of Acylhydrazones[END_REF]103,104 It can used to transform the isomer of one constituent from one configuration to another in the DCL. [START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF] Furthermore, the photosensitizer type molecule can be broken to free radicals and formed again in response to light.

One example is that Herder and Lehn 83 used sensitized alkoxyamines as "photodynamic covalent bonds" because they are stable in the dark at room temperature, while they can dissociate and undergo recombination to the bound state in response to light if there is a photoactive moiety (Figure 11). By exploring the photochemical properties of this type of dynamic covalent bond, they found that the nature and efficiency of triplet energy transfer of the sensitizer to the alkoxyamine bond as well as the reversibility of the process depends greatly on the structure of the nitroxide terminus. By screening of the components, they found that dynamic network of a sensitized and a non-sensitized alkoxyamines underwent switching between thermodynamic equilibrium and a kinetically trapped out-of-equilibrium state by temperature variation and photoexcitation. This work is significant for the generation of out-ofequilibrium states of dynamic combinatorial libraries.

Adaptation to a change of environment

The reaction medium is another important factor for the adaptation behavior of DCLs.

By screening the components, the DCL can be set up either in aqueous phase or organic phase and even in multi-phase or mixed solvents. The change of the environment could also induce the adaptive behavior of the DCLs. [START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF][START_REF] Hafezi | Adaptation of Dynamic Covalent Systems of Imine Constituents to Medium Change by Component Redistribution under Reversible Phase Separation[END_REF]103 For example, in 2012, Hafezi and Lehn [START_REF] Hafezi | Adaptation of Dynamic Covalent Systems of Imine Constituents to Medium Change by Component Redistribution under Reversible Phase Separation[END_REF]

Adaptation to metal ions

Metal ions are one of the most common chemical effectors by coordination to donor atoms within the library constituents. So far, many CDLs have been constructed to achieve the adaptation and amplification of the specific constituent which binds the best with metal ions.

The metal ions have been combined with other effectors such as light or reaction medium or even two or three metal ions together to obtain multiple adaptation through addition of different effectors into the CDLs.

One good example of the adaptation to both metal ion and light irradiation of the CDL came from the work of Vantomme and Lehn in 2012. [START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF] They reported a CDL of acylhydrazones generated from two aldehydes ( 1 A, 2 A) and two hydrazides ( 1 C, 3 C) (Figure 13). The set of hydrazones underwent metalloselection on addition of Zn(II), driving the amplification of Zn( 1 A 3 C)2. While upon irradiation to the system, it caused photoisomerization of E- and light (a physical stimulus). This paves a way to the development of information storage and processing system through multiple adaptation behavior.

1 A 1 C into Z-1 A

E

Agonistic Antagonistic

1 A 2 A 1 C 3 C E 1 A 3 C 1 A 1 C 2 A 1 C 2 A 3 C
and 5), 3 amines (1, 3 and 6) and three metal cations Fe(II), Cu(I) and Zn(II) cations (Figure 14) in the mixed solvents of CD3CN/CDCl3 (4:1). The highly selective self-sorting process of this complicated system can be attributed to the strong differences in the coordination numbers and geometries of the three metals, where Cu(I) has a coordination number of 4, Zn(II) prefers

Adaptation to morphological change

A special case of the adaptation was that DCLs can also adapt to the shape switching of the molecules from one configuration to another one in response to the effector.

For instance, Ulrich, Vantomme and Lehn 39 reported the use of light and metal cation as the stimuli to trigger the change of the molecular morphology thus leading to the constitution selection in dynamic systems (Figure 15). The W-shaped dialdehyde underwent polycondensation with a diamine to form a linear polymer. When the dialdehyde was bound to a metal cation, its configuration changed from W-shape to U-shape to hold the two aldehydes closer to each other, thus favoring the formation of a macrocycle when reacting with a diamine. Thus, this system displayed reversible switching between macrocycle and polymer states upon addition and removal of metal cations. Moreover, the illumination also induced the shape switching from W to U with the switching of the isomer from E to Z due to the formation of the hydrogen bond.

Figure 15. The switching process between a polymer and a metallomacrocycle on interconversion of ligands component between "W" and "U" shapes through binding and removal of a metal ion. 39 These examples illustrated the adaptation of the DCLs build from the dynamic covalent chemistry in response to the external effectors. Among the dynamic covalent reactions, C=N formation was widely applied in building up DCLs. This prompted the chemists to develop more efficient catalysts to further accelerate dynamic covalent reactions of C=N compounds including C=N formation, transimination, and imine metathesis.

DYNAMIC COVALENT REACTIONS USING C=N COMPOUNDS

Dynamic covalent chemistry involves the chemistry of dynamic covalent reactions (DCRs), through which the different constituents could exchange their components with each other. There are currently two main types: the first is formation of dynamic covalent bonds including condensation and addition reactions; the second is exchange reactions of dynamic covalent bonds that include exchange of components from one compound to another, resulting in the recombination and formation of new compounds. The current dynamic covalent reactions commonly used in DCC are illustrated in Table 2. Here, this thesis is mainly focused on the imine chemistry.

C=N bond formation

The C=N (imine, hydrazone, acylhydrazone and oxime) bond formation is one of the most widely used reversible reactions in dynamic covalent chemistry. [START_REF] Belowich | Dynamic Imine Chemistry[END_REF]127,[141][142][143] It is generally formed from the condensation of an aldehyde and a primary amine, hydrazine, hydrazide or alkoxyamine. When X equals _, it is an imine; when X equals NH, it is a hydrazone; when X equals O, it is an oxime. While in the absence of the catalyst, the mechanism includes two important steps: one is nucleophilic attack of the aldehyde by amino group (addition); the other is the removal of water (elimination). So far, the general accepted details of the step by step mechanism are shown in Scheme 2. 144 The first step is the nucleophilic attack of the amine on carbonyl group to generate alkoxide ion; after proton transfer, the carbinolamine formed; the next step is removal of hydroxy group to generate iminium ion; the last step is deprotonation of iminium ion to form the final product imine.

Scheme 2. The reversible formation of imines, hydrazones and oxime by the condensation reaction of carbonyl compounds with amine derivatives and the mechanism.

As described above, the reaction of an aldehyde or a ketone with a primary amine is reversible. The presence of water favors the reverse reaction. Due to this dynamic feature, the original method was to use azeotropic distillation by Dean-Stark apparatus to push the reaction towards imine formation. Other studies are devoted to the synthesis of imines through addition of catalysts instead of studying the kinetics in the presence of catalysts. In 1971, Westheim 145 reported that the synthesis of ketimines and enamines is catalyzed by molecular sieves. They calculated that the half-time for the reaction of aniline and acetophenone in the presence of molecular sieves is about 15 min, while in the absence of molecular sieves or other catalysts, the reaction is very slow, with no detectable formation of ketamine in 50 h. Here, the absorbance of water greatly accelerated the kinetics of imine formation. The catalysts included nucleophilic catalysts such as pyrrolidine through iminium activation, metal salts and oxides: P2O5/Al2O3, 146

Nano-tubeTiO2, 147 CeCl3•H2O, 148 Cu(NO3)2, 70 Er(OTf)3, 149 ZnCl2, 150 Mg(ClO4)2, 150 MgSO4-Mg(ClO4)2, 150 TiCl4, [112] and some dehydrate reagents e.g. molecular sieves, 145 CuSO4 151 and even dehydrating solvents such as trimethyl orthoformate. 152 Among these, the Lewis acids activated the nucleophilic attack of the imine on the carbonyl group, while the dehydrating reagents facilitated the removal of water.

Except the synthesis of imines, extensive research has been devoted to exploring the kinetics and mechanism of imine formation and hydrolysis (the reverse reaction) in aqueous phases. [153][154][155] Given passage through the two steps of addition followed by elimination, formation can be accelerated by catalysis of either one or both steps. This has led to the identification of a wide variety of catalysts including Brønsted acids, 156,157 metal salts, aniline and some aniline derivatives, 132,158,159 secondary amine like pyrrolidine and its derivatives, 160,161 and amine buffers etc. 162

i.

Acid catalysis

The study of the hydrolysis of Schiff base indicated the susceptibility of this reaction to specific acid catalysis. Willi suggested the addition of water to the imine was rate-determining at neutral pH, 163 while Kastening et al. obtained the contradictory results which showed the decomposition of carbinolamine was rate-determining. 164 Then Jencks studied the semicarbazone formation at different pH conditions and found that there was a transition of the rate-determining step at neutral pH (water addition) and at acidic conditions (carbinolamine decomposition). 165,166 Subsequently, after systematically study of Schiff base formation in the presence of different acids as catalysts, they found that a similar result for Schiff base formation.

The rate-determining step for Schiff base formation underwent a transition from dehydration of the carbinolamine addition product at neutral pH to amine attack on the carbonyl under acidic conditions. The acid catalysed mechanism of imine formation is shown in Scheme 3.

Scheme 3. The imine formation in the presence of Brønsted acid as a catalyst.

ii.

Metal ion catalysis

With the discovery of Schiff base by Hugo Schiff, he also studied the catalysis effect of metal ions on this reaction. 124 In 2004, Chakraborti 150 reported magnesium perchlorate to be an efficient catalyst for the synthesis of imines and hydrazones. As for some other Lewis acid catalysts such as ZnCl2, TiCl4, CuSO4•5H2O and Sc(OTf)3, the same amount of Mg(ClO4)2 ( 5mol%) accelerated the condensation of less electrophilic carbonyl compounds with poorly nucleophilic amines in dichloroethane (DCE) to give the imines in excellent yields and in short times at room temperature. These results indicated that Lewis acids especially Mg(ClO4)2 could greatly accelerate the imine formation which activated the nucleophilic attack on the carbonyl group as well as the dehydrating of water. They proposed the mechanism shown in Scheme 4.

Scheme 4. The imine formation in the presence of Lewis acid as a catalyst.

iii.

Organic amine catalysis

Except acid and metal ion catalysis, the formation of hydrazone and oxime can also be catalyzed by organic amines. Jencks first reported the nucleophilic catalysis of semicarbazone formation by aniline. 159 They demonstrated that the rate-determining step for the semicarbazone formation was the formation of the Schiff base. Dawson and co-workers 132,167 reported that oxime and hydrazone formation from two unprotected peptide derivatives were both significantly accelerated by using aniline as a catalyst at pH 5.7 (Figure 16). The aqueous solubility and otherwise unreactive nature of aniline and derivatives allows for a wide application of this nucleophilic catalysis in bioconjugation and cellular labelling. The possible mechanism for organic amine as nucleophilic catalyst is illustrated in Scheme 5. Despite the acceleration of imine formation by addition of catalysts, Kool and coworkers 127,162,[168][169][170][171] explored structural effects in both aldehydes and amines and developed a series of water soluble and less toxic catalysts for the acceleration of oxime and hydrazone formation in water. Anilines with ortho-proton donors such as carboxylic acid or phosphonic acid groups were shown to give considerable rate enhancements over aniline itself in both hydrazone and oxime formation. This was interpreted as evidence that nucleophilic catalysis is combined with general acid/base catalysis in these cases.

In a summary, the catalysts for C=N formation developed up to now was listed in Table 3 including both the catalysts for imine synthesis in organic solvents and the acceleration of the kinetics of C=N formation in aqueous phase. by demonstrating the faster component exchange between the constituent species rather than their formation from the components in the presence of DCl as a catalyst.

Scheme 7. The general mechanism of transimination in the presence of an acid as a catalyst. 189,190 ii.

Metal ion catalysis

Boate and co-workers 191 reported the efficient catalysis of transimination by metal complexes of thiourea with the exchange of an imine with aniline, while it was inhibited by excess of thiourea and by chelating ligands. In the absence of the catalysts, there was no exchange at room temperature.

Chen and Chu 192 reported the catalysis of transimination with ionic liquid as a catalyst due to its weak Lewis acidity. The presence of the ionic liquid lead to about 100-fold rate enhancement of the transimination. The addition of Sc(OTf)3 further accelerated the transiminations. The proposed mechanistic hypothesis is shown in Scheme 8. These results indicated that the metal ions could coordinate with the imine and thus activating the electrophilicity of the imine, resulting in the increased stabilization of the polar, charged intermediate. This led to the rapid transimination.

Scheme 8. A mechanistic hypothesis for the transimination reaction catalyzed by a Lewis acid (LA).

In 2012, Giuseppone and Lehn 131 reported the efficient catalysis of transimination reaction of various types of C=N bonds in organic solvent by using scandium triflate. Sc(OTf)3

was acting as a Lewis acid and resulted in the acceleration factor of up to 6 × 10 5 , with the turnovers up to 3600 h -1 . Through analyzing the rates and the distribution of the reaction at equilibrium, the mechanism was proposed by the formation of a ternary intermediate where Sc(III) was simultaneously coordinated to amine and imine (as well as solvent) molecules.

Di Stefano and co-workers 187 reported the fast transimination between aromaticaromatic or aromatic-aliphatic amines in the absence of catalysts (Scheme 9). They carried out a quantitative investigation of rates of amine-imine exchange reactions from primary amines with their benzylidene derivatives in organic solvents at room temperature. The results laid the foundation for the construction of dynamic combinatorial libraries through imine exchange in organic solvents without adding acid or metal salts as catalysts.

Imine metathesis

Olefin metathesis proceeds through component exchange between olefins. Similarly, an imine can also react with another imine through exchanging their amino fragment and carbonyl component at the same time, being an imine exchange or imine metathesis reaction (Scheme 10). Unlike imine formation and transimination, imine metathesis does not proceed in the absence of a catalyst. So far, there is not a real (associative) imine metathesis. The mechanism of imine metathesis differs depending on the catalysts: acid catalysis, metal salts catalysis and organic amine catalysis. reconducted the experiments and studied the kinetics using 1 H NMR spectroscopy. They found that the imine exchange reaction proceeds by a stepwise mechanism involving the formation of an ionic intermediate. One imine is protonated in the presence of acid and then attacked by the other imine in its neutral form to give an addition product which, after cyclisation and proton transfer, undergoes elimination to give the exchanged imines. Either the absence or an excess of acid leads to no reaction. The mechanism proposed for imine exchange is shown in Scheme 11 with acid as catalyst. 134

Scheme 11. The general mechanism of acid catalysis of imine metathesis.

Similar acid catalysis of imine metathesis was developed by Kovaříček and Lehn through addition of phenol serving as the weak acid. 196 They studied the transimination in the absence of phenol and in the presence of 1 equiv. of phenol as catalyst (Scheme 12). They found that the imine metathesis was very slow in the absence of catalysts, giving only 10% conversion after 20 hours. While in the presence of 1 equiv. of phenol, the reaction was significantly accelerated. After the same time, the conversion reached equilibrium (47%). The catalysis was due to the acidity of phenolic OH.

Scheme 12. The catalysis of imine metathesis with 1 equiv. of phenol as catalyst in comparison to that in the absence of catalyst.

ii.

Metal ion catalysis

Many efforts have also been devoted to the catalysis of imine metathesis by metal ions, the accepted mechanism being shown in Scheme 13. 135,136 Bergman and co-workers 197 studied the reaction of Cp2Zr(=N-t-Bu)(THF) with N-phenyl imines to give diazametallacycles through [2 + 2] addition and the addition product could undergo exchange with external imines. This complex is very reactive, and its formation can be inhibited by high concentrations of imines while it is easily deactivated by irreversible dimerization. Meyer and co-workers 136 reported a new class of bis(imide) complexes (DME)Cl2Mo(=NR)2, initially prepared by Schrock and coworkers 198 which react with an imine to give mixed bis(imide) complexes and a new imine.

Scheme 13. The mechanism of imine metathesis in the presence of transition metal salts as catalysts. [START_REF] Hunt | Dynamic Combinatorial Libraries: New Opportunities in Systems Chemistry[END_REF] iii.

Organic amine catalysis

For reaction using an organic amine as a nucleophilic catalyst, another mechanism called amine-mediated metathesis has been proposed. It occurs between imine reactants with a sufficient quantity of an amine added to cause transimination reactions. Di Stefano and coworkers 187 have described such reactions for amines (either aromatic or aliphatic) in organic solvents. The amine released in a first step then can undergo transimination with the other imine and so on (Scheme 14). such as aniline and some aniline derivatives, 132,157,159,169,174,[199][200][201][202] protonic acids, [START_REF] Giuseppone | Protonic and Temperature Modulation of Constituent Expression by Component Selection in a Dynamic Combinatorial Library of Imines[END_REF]101,156 molecular sieves, 145,203 metal salts such as ZnCl2, 204 TiCl4, [205][206][207] CeCl3, 148 MgSO4-PPTS (PPTS = pyridinium p-toluenesulfonate), 208 CuSO4, 151 montmorillonite clay K-10 under microwave irradiation, 209 and Mg(ClO4)2 150 have been developed to accelerate one or both of these steps.

Since a catalyst does not change the position of an equilibrium, acceleration of the forward steps must be accompanied by acceleration of the reverse processes, so that catalysis is a means of converting a simple reversible reaction into one that is dynamic. Practical applications of accelerated imine formation include protein ligation in aqueous solution 175,176,210,211 and synthesis of both C=N compounds and their complexes 212 as well as building up constitutional dynamic libraries and networks in organic solvents. [START_REF] Brady | Thermodynamically-Controlled Cyclisation and Interconversion of Oligocholates: Metal Ion Templated "living" Macrolactonisation[END_REF][START_REF] Stadler | Supramolecular Reactions of Metallo-architectures: Ag2-Double-Helicate/Zn4-Grid, Pb4-Grid/Zn4-Grid Interconversions, And Ag2-Double-Helicate Fusion[END_REF][START_REF] Hsu | Self-Sorting through Dynamic Covalent Chemistry[END_REF][START_REF] Black | Catenation and Encapsulation Induce Distinct Reconstitutions within a Dynamic Library of Mixed-Ligand Zn4L6 Cages[END_REF][START_REF] Saha | Degree of Molecular Self-Sorting in Multicomponent Systems[END_REF][START_REF] Ji | Kinetically Controlled Phenomena in Dynamic Combinatorial Libraries[END_REF][21][START_REF] Mahata | From an Eight-Component Self-Sorting Algorithm to a Trisheterometallic Scalene Triangle[END_REF][START_REF] Addicott | Self-Recognition in the Coordination Driven Self-Assembly of 2-D Polygons[END_REF] Studies of the kinetics and catalysis of C=N formation in organic phases are of rather limited extent. 213 Based on the assumption that an electron withdrawing substituent would increase the electrophilicity of the carbonyl group, pyridyl-aldehyde derivatives were chosen, because the carbonyl group can be activated not only by electron withdrawing groups due to the pyridyl unit alone but further by protonation of the pyridine-N as well as by metal cation coordination to the carbonyl-O (aided by that to pyridine-N). 214 The sensitivity of 1 H NMR spectroscopy made it the preferred method for following the reactions but of course limited the choice of metal ions, at least initially, to diamagnetic species, the metal cations Ag(I) and Zn(II) therefore being selected to study their catalysis of C=N formation. Although both these cations can have various coordination numbers, 215 generally, Ag(I) prefers to form tetrahedral, 4-coordinate complexes with bidentate imines of composition ML2, 216 while Zn(II) can expand its coordination number to 6 in octahedral ML3 species where L is bidentate or ML2 species where L is tridentate. [START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF]217 The aldehydes and amino-compounds chosen for our work were therefore intended to give rise to imines in which the imine-N would be part of either bi-or tri-dentate donor units. Under the reaction conditions employed in acetonitrile solvent, we assumed, on the basis of known equilibrium constants for similar N-donor ligands, 218 that when either metal ion was present all imine present would be bound in a complex which might have the form ML(CH3CN)n x+ early in the reaction but which would ultimately attain the form ML2. Given the lability of both Ag(I) and Zn(II), 219 it was expected that formation of the complexes would be effectively instantaneous once the ligand had formed, i.e. that the rate of formation of the complexes would not affect the overall rate of the reaction, which would be limited by that of imine formation. Although the reactions in the presence of Ag(I) or Zn(II) were studied under stoichiometric and not catalytic conditions and thus amounted to observations of the rate of formation of the metal ion complexes, comparison of their rates with those of the corresponding reactions without added metal ions enabled it to be judged as to whether or not the metal ion acted as a catalyst of the imine formation.

As noted above, the mechanism proposed for imine formation involves nucleophilic addition of the amine to the carbonyl-C to give a carbinolamine intermediate which must eliminate water to give the imine. Proton transfer processes must intervene to produce this elimination but it is not clear that they are identical in both water and organic solvents. 32,[START_REF] Campbell | A Simple and Highly Effective Ligand System for the Copper I-Mediated Assembly of Rotaxanes[END_REF] In no case in the present work was any evidence obtained for the presumed carbinolamine intermediate attaining detectable concentrations, indicating that addition, not elimination, was the rate-determining step. Therefore, the results of our work on the kinetics of C=N formation and its catalysis by metal salts and an auxiliary amine in acetonitrile solvent have been interpreted on this basis. The details of these investigations follow.

RESULTS AND DISCUSSIONS

A set of three pyridine aldehydes and two compounds bearing an amino group: phenyl (A1), methyl (A2), bromo (A3)-substituted 2-pyridyl aldehyde and B1 (p-anisidine) or B2 (Nmethyl pyridine hydrazine) were selected to study the acceleration of C=N bond formation as shown in Scheme 15. The reactions were typically performed with the aldehyde and amino compound in a 1:1 ratio and at moderate concentrations (0.01 M) to have fast reaction rates and in reactions with catalysis the amine was added in an equimolar amount while the metal ions were added in half-molar amounts assuming that the reaction product would be the ML2 complex and that this complexation would drive the reactions to completion. To verify the catalyst action, the reactions were also examined with much lower catalyst concentrations more typical of usual catalyzed processes. Complexation of the metal ions by the imine products of course meant that the solvated metal ion catalyst concentration was not constant throughout the reaction, so that an approximate kinetic treatment was applied by assuming that over the first 10 % of reaction conformity to an irreversible second-order process with an effectively constant catalyst concentration would apply and indeed this appeared to be valid. The derived apparent second order rate constants provided a convenient means of comparing the effects of the catalysts in the different imine formation reactions studied. For simplicity, the formula given for each complex in the following text shows only the metal ion and the ligand bound to it, since the possible presence of bound solvent or even bound triflate anions is not relevant to the kinetic analysis (nor detectable in the 1 H NMR spectra).

Scheme 16. The possible interactions involved in the processes of C=N formation in the presence of metal ions.

Imine formation driven by metal salts

To evaluate the efficiency of metal salts as Lewis acid catalysts in imine formation processes, we studied the condensation between A1, A2 or A3 and B1, leading to the formation of the imine A1B1, A1B2 or A1B3 (Scheme 17) both in the absence and presence of AgOTf or Zn(OTf)2.

The 1 H NMR measurements (Figure 17), showed the formation of A1B1 from the condensation of A1 with B1 to be very slow. After about 250 h, the yield of A1B1 was about 92%, with an initial rate constant k1 of 1.1 × 10 -3 M -1 s -1 (entry 1 in Table 4). The time dependence of the formation of A1B1 is shown in Figure 20A. This low reactivity is a reflection of the weak nucleophilicity of the aromatic amine B1 of low basicity (pKa = 5.34) compared with aliphatic amines (pKa between 9 and 11). Note that even so the reaction proceeds to a high degree of completion, further justifying our treatment of the initial phase of reaction as an irreversible second order process. In strong contrast, in the presence of 0.5 equiv. of AgOTf, the silver complex of imine A1B1 was obtained much more rapidly, meaning that the metal cation considerably accelerates the condensation of A1 and B1 to give the imine ligand A1B1 in its coordinated form. The initial rate k1s of formation in the presence of AgOTf was 20 × 10 -3 M -1 s -1 (entry 2 in Table 4), which is ~18 times faster than that in the absence of AgOTf due to the activation of aldehyde A1 presumably through coordination to Ag(I). The evolution of the 1 H NMR spectrum during the formation of A1B1 in the presence of Ag(I) is shown in Figure 18, the yield being 95% after 45 h. The kinetic plot of this reaction is shown in Figure 20B. The formation rate of A1B1 in the presence of Zn(OTf)2 was even more strongly accelerated with the almost full formation of product completed within 4 minutes (Figure 19).

Therefore, the reaction was essentially irreversible in the presence of metal ion, justifying the kinetic treatment. The reaction rate constant k1z was 18.2 M -1 s -1 , amounting to about a 1.65 × 10 4 times acceleration compared with that in the absence of the Zn(II) salt (entry 3 in Table 4,

Figure 20D).

A similar acceleration is also observed for the formation of A2B1 or A3B1 from their components in the presence Zn(OTf)2 (Figure 20D), indicating that Zn(OTf)2 is a very efficient catalyst of the condensation reactions probably due to the strong activation of the aldehyde A1

by Zn(II) through coordination.

A1

[Ag(A1B1) 2 ] + B1 2 h 20 min

h

Figure 19. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B1 (10 mM each) and 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 minutes compared to a reference spectrum of the separately prepared constituent [Zn(A1B1)2] 2+ .

Figure 20.Plots

of the evolution of a mixture of equimolar components (A). A1/A2/A3 + B1; (B). A1/A2/A3 + B1 + 0.5 equiv. AgOTf; (C). A1 + B1 / A1 + B1 + 0.5 equiv. AgOTf / A1 + B1 + 0.5 equiv. Zn(OTf)2 as a function of time as obtained from integration of the imine CH=N proton signal in the 500 MHz 1 H NMR spectra (10 mM each, CD3CN, 25°C); (D). Values of the initial rate constants (k) for the imine formation process between A1 (A2 or A3) and B1 in the absence and presence of AgOTf or Zn(OTf)2, calculated from a fit to a second-order reaction over the first 10% of the reaction. The numbers above the columns correspond to 10 3 k for ease of comparison.

M -1 s -1 A1B1 [Ag(A1B1) 2 ] + [Zn(A1B1) 2 ] 2+ A2B1 [Ag(A2B1) 2 ] + [Zn(A2B1) 2 ] 2+ A3B1 [Ag(A3B1) 2 ] + [Zn(A3B1) 2 ] 2+ 1 12 A B C D
To investigate the dependence of the catalysis of the reaction between A1 and B1 on the concentration of Zn(II), the reaction was studied with increments in the concentration of Zn(II)

starting from a value closer to those of usual catalysis experiments (Figure 21). The experiment was done in the following way: firstly 0.05 equiv. of Zn(II) was added, it took 4 minutes to obtain the 1 H NMR spectrum and the spectrum didn't change afterwards. It indicated that the kinetics of the catalysis was very fast. Then another 0.05 equiv. of Zn(II) was added and the 1 H NMR spectrum was recorded again. Until the addition of the amount of Zn(II) reached 0.5 equiv., the aldehyde was almost fully transformed to the product. Thus, we found that on addition of only 0.05 equiv. of Zn(OTf)2, within 4 minutes the imine had formed almost fully both as free A1B1 (90%) and the remainder as its coordinated form identified by their and preformed A1B1 in the ratios 1:2 and 1:3. Initial measurements at 25°C provided only a very broad and unassignable spectrum for the 1:3 mixture, so that final measurements were made at -35°C in order to obtain better resolution (Figure 22). At both 25 and -35°C, the 1:2 mixture showed sharp signals consistent with the presence of a single species, either tetrahedral [Zn(A1B1)2] 2+ or the C2-symmetric isomer of [Zn(A1B1)2(CH3CN)2] 2+ . At -35°C, the spectrum of the 1:3 mixture still showed some degree of signal broadening and some slight shifting of the coordinated ligand signals but most obvious was the presence of signals due to uncoordinated ligand, all these observations being consistent with at most very limited formation of a [Zn(A1B1)3] 2+ species. To ensure that all product imine was bound to the metal ion, thus simplifying the spectra, all reaction mixtures involving metal ion catalysis were made up with the composition aldehyde: amine: metal in a 1:1:0.5 ratio, the sharp signals observed in the catalysis experiments with Ag(I) confirming that this was a valid procedure for both metal ions. That the species in solution in a 2:1 mixture of A1B1 and Zn(OTf)2 is most probably the C2-symmetric isomer of octahedral [Zn(A1B1)2(CH3CN)2] 2+ is indicated by the observation that this is the form of [Zn(A1B1)2(CF3SO3)2] found by an X-ray structure determination on the complex crystallised from acetonitrile by the addition of diethyl ether (Figure 23). [a] In all these entries, aldehyde (10 mM), amine (10 mM), AgOTf or Zn(OTf)2 (5 mM), at 25°C, in CD3CN, monitored by 1 H NMR. [b] No catalyst was added. [c] Time for 50% completion of the reaction. [d] Time for 10% completion of the reaction. [e] The rate constant k has been calculated from a fit to a second-order reaction over the first 10% of the reaction. The values are listed as 10 3 k for ease of comparison. [f] Not applicable

To explore the effect of different substituents on the pyridyl aldehyde on the kinetics of the C=N formation, similar experiments involving A2 or A3 with B1 were studied both in the absence and presence of AgOTf and Zn(OTf)2.

As shown in Figure 24, the formation of the A2B1 from its components A2 and B1 is also very slow (95%, 246 h) and similar to that of A1B1. The rate constant is 0.64 × 10 -3 M -1 s -1 (entry 3 in Table 4). It indicated that the replacement of phenyl by methyl group did not have great effect on the reactivity of the aldehyde. The formation of A3B1 is much faster (95%, 12 h, rate constant 12 × 10 -3 M -1 s -1 , Figure 9) probably due to the activation of the aldehyde by the electron-withdrawing bromo substituent. The kinetic curves for the formation of A2B1 and A3B1 are shown in Figure 20A. would considerably exceed that of the imine, this is consistent with the initial formation of the 1:1 complex, [Ag(A2B1)(CH3CN)2] + . After 44 hours, the reaction was almost complete with a rate constant (k2s) of 14 × 10 -3 M -1 s -1 (entry 5 in Table 4). The acceleration factor for the concentration of Ag(I) used was approximately 22. An X-ray structure determination for the complex [Ag(A2B1)2] + [CF3SO3] -(Figure 27) shows the cation to have a flattened tetrahedral coordination geometry, which presumably would also be the case for the 1:1 complex. Under the same conditions but with A3 instead of A2 as reactant, the acceleration of the condensation due to the presence of Ag(I) was rather slight. The rate constant was k3s 44 × 10 -

10 min 5 h 44 h 2 h [Ag(A2B1) 2 ] + B1 A2
of the silver cations (k3 = 12 × 10 -3 M -1 s -1 ) by a factor of only 4. Once again, small shifts in the 1 H NMR spectral peaks for the coordinated product as the reaction progressed were consistent with the transition from a 1:1 to a 1:2 complex. The single crystal structure of 29) showed the cation to again have a flattened tetrahedral coordination geometry. and9 in Table 1). The rate constants for the formation of [Zn(A2B1)2] 2+ and [Zn(A3B1)2] 2+ were k2z ≥ 18.5 M -1 s -1 and k3z = 33 M -1 s -1 , respectively, amounting to acceleration factors of about 2.89 × 10 4 and 2.75 × 10 3 . These are in fact minimum values since reaction was almost complete when the first 1 H NMR spectrum was obtained, and the rate constants could not be accurately estimated. No marked dependence of the rates on the nature of the aldehyde substituents was apparent.

[Ag(A3B1)2] [CF3SO3] -(Figure

A3 Hydrazone formation driven by metal salts

Many efforts have already been made to study the catalysis of hydrazone formation, which is generally a much slower reaction than that of imine formation. 101 Catalysts that have been exploited for the acceleration of this reaction include aniline and aniline derivatives, 132,221,222 Brønsted acids 223 and amine buffers, 224 metal ion which have been widely applied in biological processes such as fabrication of metal complexes, 223,225 protein ligation, 180,211 as well as constitutional dynamic libraries. [START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Men | Multiple Adaptation of Constitutional Dynamic Networks and Information Storage in Constitutional Distributions of Acylhydrazones[END_REF][START_REF] Vantomme | A Light-Induced Reversible Phase Separation and Its Coupling to a Dynamic Library of Imines[END_REF][START_REF] Men | Higher Order Constitutional Dynamic Networks[END_REF]226,227 Kinetic studies have been largely focussed on aqueous systems where the reaction is somewhat unfavorable, 169,221,228,229 so the present work was firstly directed towards the study of its catalysis in organic solvents.

Similar experiments to those just described were performed using the same sets of components A1 (A2 or A3) and hydrazine B2 in the absence and presence of metal salts [Ag(I)

and Zn(II)] (Scheme 18). The evolution of the 9 reactions was followed by 1 H NMR spectroscopy at 25°C in CD3CN. , k1s', k1z', k2', k2s', k2z', k3', k3s', k3z' are the initial formation rate constants, their values being estimated from the formation of 10% product using a second order kinetic equation.

The 1 H NMR spectra show that the formation of hydrazone A1B2 is very slow (Figure 32). After 154 hours, the reaction resulted in about 95% A1B2 formation, showing B2 to be a weak nucleophile. On addition of 0.5 equiv. of Ag(I), the formation of the hydrazone complex [Ag(A1B2)2] + became much faster (Figure 33, 95%, 18 h, entry 2 in Table 5) than that of the ligand A1B2. The rate constants were 1.1 × 10 -2 M -1 s -1 and 9.7 × 10 -4 M -1 s -1 in the presence and absence of AgOTf respectively, with a rate acceleration factor of 19 due to the presence of AgOTf. Note that in this system, the coordination of Ag(I) with B2 was clear from shifts in the NMR spectra when AgOTf was added to a solution of B2 alone. This would have partially reduced the amount of Ag(A1) + that could form and slowed reaction both for this reason and because bound B2 could not act as a nucleophile. Once again, small shifts in the bound ligand resonances as the reaction proceeded were consistent with the transition from a 1:1 to a 2:1 complex. In the presence of 0.5 equiv. of Zn(OTf)2, formation of the hydrazone in its complexed forms was again accelerated (Figure 34, 95%, 62 h, k2z = 7.5 × 10 -3 M -1 s -1 , entry 3 in Table 5) In the presence of 0.5 equiv. of Ag(OTf), the silver complexes [Ag(A2B2)2] + and [Ag(A3B2)2] + formed much more rapidly (entries 5 and 8 in ) than did the free ligands A2B2

although
and A3B2 from their components A2 + B2 and A3 + B2 (entries 4 and 7 in Table 5) The evolution of the 1 H NMR spectra during the four experiment is shown below (Figure 36 to for the two sets of reactions respectively (Table 5). To see if similar responses to changes in the aldehyde structure would occur with Zn(II), these experiments were repeated with Zn(OTf)2 in place of Ag(OTf). The 1 H NMR spectral monitoring (Figure 40) showed [Zn(A2B2)2] 2+ again formed faster (entry 6 in Table 5) than did the free ligand (Figure 36, entry 4 in Table 5), with an acceleration factor of 19 (Table 5), the same as found for the same concentration of Ag(I). The single crystal X-ray structure of [Zn(A2B2)2](CF3SO3)2.CH3CN (Figure 41) again shows the Zn(II) adopts an octahedral 6coordination. In contrast, the formation of the bound ligand as [Zn(A3B2)2] 2+ (entry 9 in Table 5) was slower than that of the free ligand A3B2 (entry 7 in Table 5), as seen from the 1 H NMR spectra (Figure 37 and Figure 42). Suspecting that this inhibitory effect might have been due to coordination of B2 to Zn(II), the interactions between these two species alone was examined in more detail. The separately prepared complex [Zn(B2)2](CF3SO3)2 gave an NMR spectrum (Figure 45) in which the peaks matched those observed immediately after preparing the reaction mixture for the rate study. Titration of Zn(OTf)2 into a solution of B2 in acetonitrile (Figure 46) provided evidence for the formation of at least two complexes. With 0.1 equiv. of Zn(II) all of the peaks became very broad and new peaks appeared. At 0.2 equiv. added, the peaks became even broader, while peaks assigned to free B2 decreased in intensity and the new peaks started to increase. Addition of 0.3 equiv. of Zn(II) led to peak sharpening and when the amount of Zn(II) added reached 0.5 equiv., the peaks became very sharp. These observations indicate that it must be possible to form a reasonably stable [Zn(B2)2(CH3CN)2] 2+ species and that presumably a 1:1 complex would form on further additions of Zn(II). The presence of the 2:1 species in solution was confirmed by mass spectroscopy (Figure 47). A1/A2/A3 + B2 + 0.5 equiv. AgOTf; (C). A1/A2/A3 + B2 + 0.5 equiv. Zn(OTf)2; (D). A1 + B2, A1 + B2 + 0.5 equiv. AgOTf and A1 + B2 + 0.5 equiv. Zn(OTf)2; (E). A2 + B2, A2 + B2 + 0.5 equiv. AgOTf and A2 + B2 + 0.5 equiv. Zn(OTf)2; (F). A3 + B2, A3 + B2 + 0.5 equiv. AgOTf and A3 + B2 + 0.5 equiv. Zn(OTf)2 as a function of time as obtained from integration of the imine CH=N proton signal in the 500 MHz 1 H NMR spectra (10 mM each, CD3CN, 25°C).

Figure 44.

Values of the initial rate constants (k) for the hydrazone formation process between A1, A2 or A3 and B2 (Scheme 18) in the absence and presence of metal salts AgOTf or Zn(OTf)2 in CD3CN at 25°C, calculated from a fit to a second-order reaction over the first 10% of the reaction. The numbers above the columns correspond to 10 3 k for ease of comparison.

M -1 s -1 A1B2 [Ag(A1B2) 2 ] + [Zn(A1B2) 2 ] 2+ A2B2 [Ag(A2B2) 2 ] + [Zn(A2B2) 2 ] 2+ A3B2 [Ag(A3B2) 2 ] + [Zn(A3B2) 2 ] 2+ 1 2 3 14
Table 5. Kinetic features of the reactions between aldehyde A1, A2 or A3 and hydrazine B2 in the absence and presence of metal salts.

Entry [a] Reaction Catalyst 0.5 equiv. [a] In all of these entries, aldehyde (10 mM), hydrazine (10 mM), AgOTf or Zn(OTf)2 (5 mM), at 25°C, in CD3CN, monitored by 1 H NMR. [b] No catalyst was added. [c] Time for 50% completion of the reaction. [d] Time for 10% completion of the reaction. [e] The rate constant k has been calculated from a fit to a second-order reaction over the first 10% of the reaction. The values are listed as 10 3 k for ease of comparison. [f] Not applicable.

Product t50[h]

[c] t10[h] [d] k [e] /10 -3 M -1 s -1 Acceleration Factor 1 A1 + B2 _ [b] A1B2 21

Synergistic effects of metal salts and an auxiliary amine

The results above indicate that metal salts enhanced the rates of both imine and hydrazone formation, the effect being larger on imine formation than on hydrazone formation in the cases investigated. Given also that these reactions are known to be susceptible to nucleophilic catalysis by bases such as aniline, an obvious question was that of whether their conduct in the k1a, k1as, k1az, k1i, k1iz, k2a, k2as, k2az, k3a, k3as, k3az are the initial corresponding formation rate constants calculated from the formation of 10% product using a second order kinetic equation. For the structures of A1B1, and [Zn(A1B1)2] 2+ see Scheme 15.

i.

Synergistic effect for the formation of complex of A1B2

The separate reaction of a mixture of the two components A1 + B2 (10 mM each) was followed by 1 H NMR either in presence of amine B1 or metal salt as well as both amine B1 and metal salt as shown in entries 1 to 8 in Table 6. In the presence of only amine B1 (1.0 equiv.), A1B2 was formed (2.4 × 10 -3 M -1 s -1 , 50 h, entry 2 in Table 6, Figure 48), with a threefold acceleration of the reaction in comparison to the reaction A1 + B2 in the absence of the amine (0.97 × 10 -3 M -1 s -1 , 162 h, entry 1 in Table 6, Figure 32). In the previously described experiments with AgOTf or Zn(OTf)2 alone as catalysts (at half the concentration of the amine here), accelerations by factors of 14 and 8 were observed, the corresponding rate constants being 14 × 10 -3 M -1 s -1 and7.5 × 10 -3 M -1 s -1 respectively (entries 2 and3 in Table 6; 18 h and62 h, Figure 33 andFigure 34). Here, AgOTf was the slightly better catalyst, perhaps because of differences in the stability of the complexes of B2 with the two cations. The addition of the amine B1 to the reaction mixture containing AgOTf had very little effect on the rate of the reaction (entries 3 and 5 in Table 6, Figure 33 and Figure 49). The rate constants are 16 × 10 -3 M -1 s -1 and 14 × 10 -3 M -1 s -1 in the presence and absence, respectively, of B1 and are essentially identical within experimental error. The kinetic curves are shown in In contrast, a strong effect was observed when B1 was combined with Zn(OTf)2 (entry 6 in Table 6; Figure 50). After just 4 minutes, the mixture contained about 25% of A1B1 in its complexed form, 29% of free A1, 70% of free B1 and 64% B2 in its coordinated form together Obviously, rather unsymmetrical species such as [Zn(B2)x(A1B1)y(CD3CN)z] 2+ might be present at certain stages. After about 2 hours, the zinc complex [Zn(A1B2)2] 2+ was fully formed, leaving free B1 in the solution. The formation rate constant was about 0.61 M -1 s -1 , which is a roughly estimated value calculated with regard to the loss of the aldehyde A1 for easier comparison of different reactions (98%, 2 h, entry 6 in, Figure 52). Thus, the reaction rate was markedly increased when both metal cation and amine were added simultaneously to the reaction of A1 with B2, with an acceleration factor of 630 compared to the formation of A1B2 from A1 + B2 alone. In order to slow down the reaction and define the evolution of the reaction especially in the beginning period where the 25°C 1 H NMR spectrum was very broad, the reaction was performed starting at the low temperature of -35°C then incrementing it to +25°C in steps of 10 degrees (Figure 51). At each temperature, the 1 H NMR spectrum was recorded 5 minutes after the temperature was attained. At -35°C, the first spectrum recorded showed about 12% A1, 14%

Zn(II) complex of A1B1, 70% A1B1 with broad signals, 82% B2 in its coordinated form and 20% free B1 to be present. A1B1 reached a maximum of 90% at -25°C. In passing to 15°C, A1

and [Zn(A1B1)2] 2+ decreased progressively and disappeared, while [Zn(A1B2)2] 2+ appeared and increased up to complete formation along with the release of free B1 and the decrease and disappearance of A1B1 and B2. These results indicated that the [Zn(A1B1)2] 2+ formed very rapidly at the beginning behaved as an activated species which reacted with B2 to form [Zn(A1B2)2] 2+ . Thus, metal salts and an amine together can strongly enhance hydrazone formation.

A1 + B2 A1 + B2 + Ag(I) A1 + B2 + Zn(II) A1 + B2 + B1 A1 + B2 + B1 + Ag(I) A1 + B2 + B1 + Zn(II) A1B1 + B2 [Zn(A1B1) 2 ] 2+ + B2
Table 6. Kinetic features of the reactions between aldehyde A1 and hydrazine B2 in the absence and presence of metal salts separately as well as in the presence of both B1 and metal salts together and control reactions of A1B1 with B2 and [Zn(A1B1)2] 2+ with B2.

Entry [a] Reaction Catalyst 0.5 equiv.

Product t50[h] [c] t10[h] [d]

k [e] /10

A1B1 + B2 _ [b] A1B2 1.0 0.08 39 40 [b] 8 [Zn(A1B1)2] 2+ + B2 _ [b] [Zn(A1B2)2] 2+ 0.16 ≤0.08 ≥640 ≥660 [b]
[a] In all entries, aldehyde (10 mM), amine or hydrazine (10 mM), AgOTf or Zn(OTf)2 (5 mM), at 25°C, in CD3CN, monitored by 1 H NMR. [b] Transimination experiments; no catalyst added; the acceleration factors correspond to the reaction of B2 with the imine A1B1 free (entry 7) or complexed (entry 8) compared to the reaction of B2 with the aldehyde A1 (entry 1). [c] Time for 50% completion of the reaction. [d] Time for 10% completion of the reaction. [e] The rate constant k has been calculated from a fit to a second-order reaction over the first 10% of the reaction (error on calculated rate constant of about 5%). The values are listed as 10 3 k for ease of comparison. [f] Not applicable.

To analyze the possible origins of this synergistic catalysis, the following experiments were conducted: a) Starting from the preformed imine A1B1, addition of 0.5 equiv. of Zn(OTf)2, led to the immediate and full formation (99%) of the zinc complex of [Zn(A1B1)2] 2+ as indicated by its imine signal at 9.0 ppm (Figure 53). On addition of 1 equiv. B2, some of the signals in c) We then checked if A1B2 formation was faster from the transamination reaction of A1B1 with B2 than from condensation of A1 and B2. As described earlier, when just A1 and B2 were mixed, A1B2 was obtained after about 162 h (entry 1 in Table 6), When B2 was added to A1B1, A1B2 was obtained in about 10 h (99%; entry 7 in Table 6; Figure 55) with a rate constant of 3.9 × 10 -2 M -1 s -1 amounting to 40-fold acceleration of the formation of A2B2 from its components A2+B2. This result indicates that the hydrazone A1B2 formed more rapidly from the preformed A1B1 and B2 than from A1 + B2, implying that A1B1 is more reactive as an electrophile than A1, an interesting result perhaps indicative of differences in proton transfer rates in the aminal addition intermediate than in the carbinolamine. There is a very marked synergistic co-catalytic effect on simultaneous addition of Zn(II)

and B1 to the A1 + B2 mixture which leads to a much faster formation of the [Zn(A1B2)2] 2+ complex than when either Zn(II) or B1 is added separately (2 h versus 62 h or versus 50 h respectively; see entries 3, 4 and 6 in Table 6).

Particular observations which bear upon the mechanism of the co-catalysis described above are:

1) The formation of the imine A1B1 from A1 + B1 is very slow (entry 1 in Table 4, 1.1 × 10 -3 M -1 s -1 ).

2) The formation of the hydrazone A1B2 is very slow but increases along the sequence: i)

A1 + B2 (entry 1 in Table 4, 0.97 × 10 -3 M -1 s -1 ); ii) A1 + B1 + B2 (entry 2 in Table 6, 3.2 × 10 -3 M -1 s -1
) a little faster with no A1B1 observed; iii) A1B1 + B2 (entry 7 in Table 6, 16.5 × 10 -3 M -1 s -1 ).

3) The formation of the imine complex [Zn(A1B1)2] 2+ from A1 + B1 + Zn(II) (entry 3 in Table 4, 18.2 M -1 s -1 ) is much faster than that of the imine A1B1 in the absence of Zn(II), being complete when the first spectrum is measured (about 4 min; 98%) giving an acceleration factor at least 1.65 × 10 4 .

4) The formation of the hydrazone-based zinc complex [Zn(A1B2)2] 2+ from A1 + B2 + Zn(II) (entry 3 in Table 4, 5.5 × 10 -3 M -1 s -1 ) is comparable to that of the hydrazone A1B2 from A1 + B1 + B2 (2ii above), both being faster (about 6 times and 3 times) than that of the hydrazone A1B2 from A1 + B2 (see 2i).

5) The formation of [Zn(A1B2)2] 2+ from [Zn(A1B1)2] 2+ + B2 is very fast (entry 8 in Table 6, 57 × 10 -3 M -1 s -1 ).

6) The formation of the hydrazone-based zinc complex [Zn(A1B2)2] 2+ from A1 + B1 + B2

+ Zn(II) is very fast (entry 6 in Table 6, 54 × 10 -3 M -1 s -1 ).

The most important aspects of these results are that i) the formation of the imine complex [Zn(A1B1)2(CF3SO3)2] is by far the fastest reaction of all; ii) B1 and Zn(II) exert independently a moderate effect on the formation of respectively the ligand A1B2 itself and of its complex

[Zn(A1B2)2] 2+ ; iii) when BOTH are present, they exert a very strong synergistic catalysis effect on the formation of this same complex.

These observations can be rationalized if i) the complexed imine A1B1 is the active species in the process, perhaps in the form of [Zn(A1B1)2(CH3CN)2] 2+ ; ii) the C=N bond of imine A1B1 is more reactive than the C=O group of aldehyde A1; iii) the N of imine A1B1 is a better binding site for Zn(II) than the O of C=O in A1. ii.

Synergistic effect for the formation of complexes of A2B2

To see if synergism applied in catalysis of the formation of the ligand A2B2, another set of experiments with A2 + B2 in the presence of B1 alone (Figure 56, Table 7), and B1 and 0.5 equiv. of either AgOTf (Figure 57) or Zn(OTf)2 (Figure 58) was also conducted. Similar results were obtained. The kinetic curves and rate constants are shown in Figure 59 and Table 7.

In the presence of only B1 (entry 4 in Table 7), the formation of A2B2 was 3 times faster than for A2 + B2 alone (entry 1 in Table 7). Reactions of A2 + B2 in the presence of Ag(I) or Zn(OTf)2 both gave 11 times acceleration (entries 2 and 3 in Table 7). In the presence of both Ag(I) and B1 (entry 5 in Table 7), the reaction was moderately accelerated in comparison to the formation of A2B2 alone with 15 times acceleration, a comparable value to that of A2 + B2 in the presence of only Ag(I) (entry 2 in Table 7). The formation of hydrazone A2B2 as its Zn(II) complex was significantly accelerated in the presence of co-catalysts Zn(II) and p-anisidine (B1), with a rate constant of 0.24 M -1 s -1

(entry 6 in Table 7). The acceleration factor of this synergistic catalysis is 421 times that of the formation of A2B2 alone (5.7 × 10 -4 M -1 s -1 ). The 1 H NMR spectra again showed broadened signals in the early stages of reaction, presumably due to relatively slow exchange between different Zn(II) complexes. After less than 3 hours, [Zn(A2B2)2] 2+ was almost fully formed (Figure 58). [a] In all these entries, aldehyde (10 mM), amine or hydrazine (10 mM), AgOTf or Zn(OTf)2 (5 mM), at 25°C, in CD3CN, monitored by 1 H NMR. [b] No catalyst was added. [c] Time for 50% completion of the reaction. [d] Time for 10% completion of the reaction. [e] The rate constant has been calculated from a fit to a second-order reaction over the first 10% of the reaction. The values are listed as 10 3 k for ease of comparison. [f] Not applicable.

iii. Synergistic effect for the formation of complex of A3B2

When A1 was replaced by A3, similar sets of experiments A3 + B2, A3 + B2 + B1, A3 + B2 + B1 + AgOTf and A3 + B2 + B1 + Zn(OTf)2 were conducted and the kinetic curves and rate constants are shown in Figure 63 and Table 8. . initial rate constant (k) for the hydrazone formation process between A3 and B2 (Scheme 19) in absence of catalyst and in presence of B1 or a metal salt, AgOTf or Zn(OTf)2 separately, as well as B1 and AgOTf or B1 and Zn(OTf)2 together as co-catalysts along in CD3CN at 25°C. The numbers above the columns correspond to 10 3 k for ease of comparison.

Table 8. Kinetic features of the reactions between aldehyde A3 and hydrazine B2 in the absence and presence of metal salts separately as well as in the presence of both B1 and metal salts together [a] In all these entries, aldehyde (10 mM), amine or hydrazine (10 mM), AgOTf or Zn(OTf)2 (5 mM), at 25°C, in CD3CN, monitored by 1 H NMR. [b] No catalyst was added. [c] Time for 50% completion of the reaction. [d] Time for 10% completion of the reaction. [e] The rate constant has been calculated from a fit to a second-order reaction over the first 10% of the reaction (error on calculated rate constant of about 5%). The values are listed as 10 3 k for ease of comparison. [f] Not applicable.

Entry [a] Reaction Catalyst Product t50[h] [c] t10[h] [d] k [e] /10
The formation of A3 + B2 in the absence of any catalyst (entry 1 in Table 8) is much faster than A1 + B2 (entry 1 in Table 6), possibly due to the electron-withdrawing character of the

A B

bromo group of A3. The reaction A3 + B2 in the presence of AgOTf gave an acceleration factor of 2.1, while in the presence of Zn(OTf)2, the formation of zinc complex of A3B2 is even slower than the formation of A3B2 from A3 and B2. This is probably an effect of the strong coordination of B2 by Zn(II). In the presence of co-catalysts B1 and AgOTf (entry 5 in Table 8), the formation of silver complex of A3B2 is accelerated by a factor of 23 compared to that without any catalyst and 10 compared to that with Ag(I) alone, indicating that there is synergistic effect of B1 and AgOTf. The simultaneous operation of both B1 and Zn(OTf)2 induced a large acceleration by a factor of 85 relative to the uncatalyzed process (entry 6 in Table 8), with a rate constant of 0.52 M -1 s -1 .

iv. Synergistic effect of the three co-factors AgOTf, Zn(OTf)2 and B1

When the reaction A1 + B2 (10 mM each) was run in presence of the three co-factors, B1

(10 mM) together with both AgOTf (5 mM) and ZnOTf (5 mM), the silver complex of the imine A1B1 was already formed (92%) after only 10 minutes, with a similar amount of the Zn(II) complex of B2 being present, in strong contrast to the very slow formation of A1B1 in the absence of metal cations. The mixture rearranged by component exchange to form the zinc

complex [Zn(A1B2)2] 2+ , giving the final distribution of 8% [Ag(A1B1)2] + , 92% [Zn(A1B2)2] 2+
and free B1 (13 h; Figure 64). Thus, in presence of both silver and zinc cations, the silver complex of A1B1, [Ag(A1B1)2] + is the kinetic product and then the set slowly changes (13 hours) to the zinc complex of A1B2, [Zn(A1B2)2] 2+ as thermodynamic product.

The set of the reactions could proceed as follows: i) Zn(II) was mostly coordinated by B2 in the beginning; ii) very small amount of free Zn(II) catalyzed the fastest formation of A1B1;

iii) Ag(I) picked up free A1B1 to form the silver complex of A1B1; iv) the formation of the hydrazone A1B2 drives the exchange reaction between [Ag(A1B1)2] + and [Zn(B2)2] 2+ , resulting in the final formation of [Zn(A1B2)2] 2+ and the release of B1 together with Ag(I).

These results display a striking example of a more rapidly formed and simpler kinetic output (the silver complex) resulting from competition within a mixture of higher complexity (five entities: three molecular components A1 + B2 + B1 and two metal ions), thus extending to the kinetic arena the simplification of behavior noted above on the thermodynamic scene.

Catalysis of imine and hydrazone formation driven by metal salts and acid

The significant accelerations observed for the formation of imine and hydrazone ligands by stoichiometric amounts of metal salts prompted us to explore the effect of catalytic amounts.

As is reported earlier, Sc(OTf)3 can effectively catalyze transamination. 131 To evaluate the influence of metal ion catalyst charge on C=N formation with high conversion, the kinetics of the imine A1B1 and hydrazone A1B2 formation reactions were investigated in the presence of only 0.05 equiv. (5 mol%) of three metal salts AgOTf, Zn(OTf)2 and Sc(OTf)3, as well as CF3COOD (Table 9 and Figure 67-Figure 68). Several parameters were determined including the initial rate constant, the turnover frequency (TOF) and the acceleration factor. On addition of 0.05 eq. of Ag(I) (entry 2), the formation of A1B1 from its components A1 and B1 was accelerated by only a factor of 1.5 compared to the rate in the absence of the salt (entry 1), indicating that Ag(I) displayed a very weak catalytic effect on imine formation. In the presence of the same amount of Zn(II), the formation of A1B1 was greatly accelerated by a factor of 2.6 × 10 3 (entry 3). The highest rates were found in the presence of 0.05 equiv. of CF3COOD (entry 5), with a rate enhancement by a factor of 1.2 × 10 7 times over that in the absence of added acid.

The presence of 0.05 eq. of Sc(III) triflate also displayed a remarkable catalytic effect on A1B1

formation with an acceleration factor of 5.7 × 10 6 (entry 4). These results are in line with a study of the effect of different metal ions on the transamination reaction. 131 A similar set of experiments were conducted for the formation of hydrazone A1B2 (Figure 68 and Table 9). Addition of 0.05 eq. of Ag(I) to A1 + B2 produced a catalytic effect with an acceleration by a factor of 3 compared to the reaction in absence of salt (entries 6 and 7 in Table 9), an effect similar to that observed on imine formation. In presence of 0.05 eq. of Zn(II) only a small effect with a rate enhancement of 2 was obtained (entry 8 in Table 9). [a] Conditions for all these entries: aldehyde (10 mM), amine (10 mM), AgOTf or Zn(OTf)2 (5 mM), at 25°C, in CD3CN, monitored by 1 H NMR. [b] No catalyst was added. [c] Time for 50% completion of the reaction. [d] Time for 10% completion of the reaction. [e] Rate constant calculated from a fit to a second-order reaction over the first 10% of the reaction , and they are crude estimates values calculated by the loss of aldehyde in the initial stage in order for easier comparison of different reactions.

On changing the aldehyde to A2, the initial reaction rate was faster while the reaction conversion time did not change much (entry 12 in Table 9). As in the case of imine formation, Sc(III) or CF3COOD gave the hydrazone with a significant acceleration by a factor of 121 and 47 respectively (entries 9 and 10 in Table 9). The activity of Sc(III) may reflect its "oxophilic character", meaning that it forms much more stable complexes with oxygen-containing ligands than with N-donor species, so that in the mixtures it would be expected to be much less involved in inhibitory coordination of the amine than Zn(II). Finally, when both 0.05 equiv. Zn(II) and 0.05 equiv. auxiliary amine p-anisidine were added (entry 11 in Table 9, Figure 69), the formation of A1B2 was 6 times faster than that without catalysts and with Zn(II) or p-anisidine alone (Figure 68). This result further verified that Zn(II) and p-anisidine exert synergistic catalysis on hydrazone formation.

SUMMARY OF CHAPTER II

We have studied the kinetics and catalysis of a series of C=N (imine and hydrazone) formation in the presence of metal cations as well as the co-operative catalysis by metal cations

A1B1 or A2B2 [%] A1 + B1 A1 + B1 + Ag(I) A1 + B1 + Zn(II) A1 + B1 + Sc(III) A1 + B1 + CF 3 COOD A1 + B2 + Ag(I) A1 + B2 + Zn(II) A1 + B2 + Sc(III) A1 + B2 + CF 3 COOD A1 + B2 + Zn(II) + B1 A2 + B2 + Zn(II)
and an auxiliary amine. Some of the reactions were conducted both in stoichiometric and catalytic conditions to clarify the role of the metal cations in catalysis Thus, we have demonstrated a marked enhancement of the efficiency of imine and hydrazone formation by addition of metal cations [Ag(I) and Zn(II)] under stoichiometric conditions where the observed products were the complexes of the imines and hydrazones.

Under catalytic conditions, the addition of Ag(I), Zn(II) or Sc(III) metal salts or of CF3COOD resulted in acceleration of both imine and hydrazone formation. Under both stoichiometric and catalytic conditions, the effect displayed by these catalysts was much more pronounced on the formation of imines than that of hydrazones due probably to inhibitory coordination of the hydrazines by the metal cations. It has been further demonstrated that simultaneous addition of both a metal salt and an aniline derivative as auxiliary amine to the reacting components of a DCL induced a strong acceleration of the formation of the complex of the hydrazone ligand in a synergistic fashion. This was found to be dependent on the very efficient Zn(II) catalysis of imine formation. Further, simultaneous addition of an auxiliary amine as well as both a silver salt and a zinc salt resulted in a synergistic co-catalysis whereby the DCC system undergoes a switching from a kinetic product (the silver complex of an imine) to the thermodynamic product (the zinc complex of a hydrazone). This mode of co-catalysis represents a step in the implementation of two or more catalytic species, in particular in DCC, combining metallo-and organo-catalysis and acting together in a dynamic network through synergistic interconnected chemical transformations. Such effects are of much interest for DCC systems especially [2 × 2] DCLs based on chemical bond formation with differences in formation rates and thermodynamic stabilities. Such behavior shows that increasing system complexity may result in kinetically faster and thermodynamically simpler outputs, an increase in complexity leading thus to simplexity through advanced features such as competition, feedback, and synergy in constitutional dynamic system.

CHAPTER III. CONTROL OF TIME-DEPENDENT SWITCHING OF DCLS 1. INTRODUCTION

In the Chapter II, we discussed the catalysis of imine and hydrazone formation in the presence of metal cations AgOTf and Zn(OTf)2. Interestingly, the operation of Zn(II) and amine together displayed a synergistic effect on the formation of zinc complex of hydrazone. In addition, upon the simultaneous addition of three co-factors, Ag(I), Zn(II) and amine, the dynamic system underwent a switching from the kinetic product (the silver complex of imine) to the thermodynamic product (the zinc complex of hydrazone). This is a very interesting result, which is worthy to be studied in the [2 × 2] CDL.

As described earlier, a constitutional dynamic library (CDL) [START_REF] Fujii | Structural and Functional Evolution of a Library of Constitutional Dynamic Polymers Driven by Alkali Metal Ion Recognition[END_REF][START_REF] Hunt | Dynamic Combinatorial Libraries: New Opportunities in Systems Chemistry[END_REF][230][231][232][233][234][235][236][237][238] can be generated from the sets of constituents from chemical entities, where the constituents could undergo constitutional variation through reversible formation of covalent and non-covalent linkages.

The generated CDL may change the distribution of its constituents in response to physical stimuli (such as light, [START_REF] Herder | The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool To Shift Reaction Networks Out-of-Equilibrium Using Light Energy[END_REF]103,[239][240][241][242][243] temperature, [START_REF] Giuseppone | Protonic and Temperature Modulation of Constituent Expression by Component Selection in a Dynamic Combinatorial Library of Imines[END_REF][START_REF] Herder | The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool To Shift Reaction Networks Out-of-Equilibrium Using Light Energy[END_REF] pressure, [START_REF] Sobczak | Dynamic Covalent Chemistry under High-Pressure:A New Route to Disulfide Metathesis[END_REF] and various other factors [START_REF] Hafezi | Adaptation of Dynamic Covalent Systems of Imine Constituents to Medium Change by Component Redistribution under Reversible Phase Separation[END_REF][START_REF] Giuseppone | Electric-Field Modulation of Component Exchange in Constitutional Dynamic Liquid Crystals[END_REF]244,245 ) or chemical effectors (metal cations, [START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF][START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Men | Multiple Adaptation of Constitutional Dynamic Networks and Information Storage in Constitutional Distributions of Acylhydrazones[END_REF][START_REF] Ayme | Self-Sorting of Two Imine-Based Metal Complexes: Balancing Kinetics and Thermodynamics in Constitu-tional Dynamic Networks[END_REF][START_REF] Giuseppone | Driven Evolution of a Constitutional Dynamic Library of Molecular Helices toward the Selective Generation of [2 × 2] Gridlike Arrays under the Pressure of Metal Ion Coordination[END_REF][START_REF] Men | Higher Order Constitutional Dynamic Networks[END_REF]246 protons, 247,248 reactive molecules [249][250][251] and self-sorting [START_REF] Ji | Kinetically Controlled Phenomena in Dynamic Combinatorial Libraries[END_REF]102,139,[252][253][254][255][256][257] ), thus achieving the selection and adaptation. Among these effectors, metal cations are one kind of important effectors which could coordinate with C=N bond ligands, thus driving the formation of the metal complex. To be noted, they can form metal complexes with different geometries due to the specific preference of different metal cations. [START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF][START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Ayme | Simultaneous Generation of a [2 × 2] Grid-Like Complex and a Linear Double Helicate: A Three-Level Self-Sorting Process[END_REF][START_REF] Ayme | Self-Sorting of Two Imine-Based Metal Complexes: Balancing Kinetics and Thermodynamics in Constitutional Dynamic Networks[END_REF][START_REF] Ayme | Triple Self-Sorting in Constitutional Dynamic Networks: Parallel Generation of Imine-Based CuI, FeII, and ZnII Complexes[END_REF]258 This effector has been applied to achieve multiple mode of adaptation behavior as well as self-sorting of DCLs. [START_REF] Osypenko | Pattern Generation and Information Transfer through a Liquid/Liquid Interface in 3D Constitutional Dynamic Networks of Imine Ligands in Response to Metal Cation Effectors[END_REF][START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Ayme | Self-Sorting of Two Imine-Based Metal Complexes: Balancing Kinetics and Thermodynamics in Constitu-tional Dynamic Networks[END_REF][START_REF] Ayme | Simultaneous Generation of a [2 × 2] Grid-Like Complex and a Linear Double Helicate: A Three-Level Self-Sorting Process[END_REF][START_REF] Men | Higher Order Constitutional Dynamic Networks[END_REF][START_REF] Ayme | Triple Self-Sorting in Constitutional Dynamic Networks: Parallel Generation of Imine-Based CuI, FeII, and ZnII Complexes[END_REF]258 The adaptation of the DCLs were usually performed upon the equilibrium. The generated distribution of the constituents resulted from the thermodynamic control. However, it was very interesting to study the out-of-equilibrium states or far-from equilibrium states of the DCL where the adaptation is under kinetic control. The establishing of such system relies on the variation of the effectors to drive the system towards the out-of-equilibrium states.

One way could be to use light as driving force because the photoisomerization would generate the kinetic product while the heating would lead to the thermodynamic product. As noted by Lehn, such a system could be used to generate the assembly of synthetic receptors (Figure 70). [START_REF] Lehn | Perspectives in Chemistry -Aspects of Adaptive Chemistry and Materials[END_REF] The DCL can be utilized in response to binding with a bioactive substance to achieve the selective recognition. This selection can occur in two ways. One is that the photoresponsive receptor would generate a kinetically trapped out-of-equilibrium state to amplify the constituent which would fit the receptor best (kinetic selection). The other is that the receptor amplifies/favors the expression of the constituent/key that binds best to it (thermodynamic selection). 249 The out-of-equilibrium state and equilibrium state could also be transformed between each other through light irradiation and high temperature conditions. The above kinetic behavior of the DCL allows to generate the out-of-equilibrium states.

In another way, the kinetic product could also be trapped and thus leaving the DCL to generate the selection of the kinetic product from the DCL. These methods can be, for instance, precipitation-induced organization of DCLs, distillation-induced selection of DCLs, acetylation and other irreversible reactions. [START_REF] Ji | Kinetically Controlled Phenomena in Dynamic Combinatorial Libraries[END_REF] One example of the kinetic control of the DCLs was from Miljanić and co-workers [START_REF] Lirag | Oxidative Kinetic Self-Sorting of a Dynamic Imine Library[END_REF] who reported the kinetic self-sorting of DCLs by use of the method of distillation (Figure 71).

They build up a series of [2 × 2], [3 × 3], [4 × 4], [5 × 5] DCLs. The main strategy is to screen the aldehydes and amines to generate the imine product with different boiling points. According to the [2 × 2] DCL, the high molecular mass of the imine also had a higher boiling point. For a 72). [START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF] The equilibrated The kinetics study of the reactions within the DCLs especially C-N formation and C/N exchange was thus necessary to control the kinetic behavior of the DCLs. From the previous work, 101 it is found that imines 126 form very fast, while oximes, 165,167,201,[259][260][261][262][263] hydrazones 158,168,174,[264][265][266] and acylhydrazones 267,268 form slowly but have higher thermodynamic stabilities at equilibrium. 143,223 Therefore, the formation of C=N bonds gives out a wide range of reaction rates 127,132,157,170,175,180,224 and thermodynamic stabilities. 101,143 Since thermodynamics was the main target for the DCLs studied before, the kinetic aspect of DCLs has rarely been studied and reported. [START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF] Here in our cases, by introducing these different C=N bond compounds into a [2 × 2] DCL, these differences in the relative rates of C=N

RESULTS AND DISCUSSIONS

As seen in

Kinetic switching of a constitutional dynamic library in the absence of metal ions i. DCL[1] generated from the four components A3, A4, B4, B5

The type of pyridine aldehyde (A1 to A4) is known to be more reactive than that of benzaldehyde (A5 to A8) and can also generate an NN bidentate or NNO tridentate coordination site for metal cation binding by reaction with amines or hydrazides. As mentioned above, benzylamines (B3), O-benzylhydroxylamine (B4) or N-methylbenzohydrazide (B5) were chosen due to the differences in the thermodynamic stabilities of their C=N products. To start with, the four relatively simple components A4, A5, B3, B4 were selected to set up the first set of DCL. We were curious to know if the DCL with this combination of the four components would achieve the goal for kinetic switching of CDNs as designed.

1) The C=N formation from two components

Firstly, the sets of two-component experiments were studied from the four components A4, A5, B3 and B4. The separate kinetics of the formation of A4B3, A4B4, A5B3 and A5B4 were followed by 1 H NMR spectroscopy (Figure 73 to Figure 76). The corresponding kinetic curves of these four reactions are displayed in Figure 77.

From the 1 H NMR spectra and kinetic curves, we can observe that the formation of A4B3 from its components A4 and B3 was very fast. After 45 minutes, the imine A4B3 was almost fully formed. While the formation of A4B4 from its component A4 and B4 was very slow, the amount of oxime A4B4 reached 65% after about 155 hours. These two experiments indicated that the imine formation (A4B3) is much faster than the oxime formation (A4B4). This is mainly due to the higher nucleophilicity of B3 compared with B4. When similar experiments were run for A5, the formation of A5B3 was slower than the formation of A4B3 due to the low reactivity of A5 in comparison with A4. As expected, the formation of A5B4 was also much slower than that of both A4B4 and A5B3. Therefore, these results implied that the imine formation is much faster than oxime formation and the pyridyl-aldehyde is much more reactive than benzaldehyde. To further verify the reactivity of A5 (less reactive than A4), a similar set of experiment [A5 + B3 + B4] was performed to explore the design and the kinetics (Figure 79). As expected, by replacing A4 by A5, the reaction proceeded much more gradually and slower (see Figure 81B for the kinetics curve), indicating a clear observation of the reaction behavior within the first hours. In agreement with the set of experiment [A4 + B3 + B4], the imine A5B3 formed first as the kinetic product and the then transformed to the oxime A5B4 as the thermodynamic product. This observation indicated that A4 should be more reactive than A5 even in the [2 × 2] DCL where the four components A4, A5, B3 and B4 are all present, which will be discussed later. 3) The kinetic switching of DCL [1] from of four constituents generated from four components

The DCL [1] was thus generated from equimolar amount of the four components A4, A5, B3, B4 in CD3CN at room temperature. The evolution of the composition of components and generated constituents of the DCL [1] was monitored by 1 H NMR spectroscopy as a function of time (Figure 82).

After about half an hour, A4B3 was detected as the main product with the constituents A4B4, A5B3 and A5B4 formed in a biased distribution of 36%, 13%, 6%, 1% as well as 44%

of free A5, 37% of free B4 and 10% free B3 respectively (Scheme 23). Therefore, A4B3 was the overwhelming kinetic product of the DCL at the initial stage. Due to the agonist amplification manner of DCLs, the large amount of A4B3 formation should have amplified its agonist constituent A5B4. However, the formation of A5B4 was not observed at this moment because of the low reactivities of A5 and B4 (kept unreacted). This biased kinetic distribution can be attributed to the faster imine A4B3 formation with respect to the oxime A4B4 formation.

These results were further proven by the results of the competitive reactions above for i) A4

with B3 and B4 (Figure 81A); ii) A5 with B3 and B4 (Figure 81B) as well as iii) B3 with A4

and A5 (Figure 81C). They demonstrated that A4 is more reactive than A5 while B3 is more reactive than B4. Then, as the exchange reaction proceeded, the amount of imine A4B3 decreased, while the oxime product A4B4 was increased with amplification its agonist constituent A5B3. The initial amounts of the components were almost fully consumed after 15 hours and only the four expected constituents were present with the final distribution of 14%/36%/35%/13% for the constituents A4B3, A4B4, A5B3, A5B4, with 2% of free A5

respectively. The kinetic curve of the variation of the constitution of the DCL is presented in III1 to Table III7, Table III12-Table III15.

iii. DCL[3] generated from the four components A1, A6, B3, B5

From the results above, the design and success of such time-dependent switching system relies to large content on the rates of C=N formation where the screening of the aldehydes and amino compounds are of key importance to the kinetic aspects. Since the use of imines and oximes works well due to the differences in the kinetic and thermodynamic properties, similar behavior should also be observed by use of hydrazones due to the apparent difference in rates and stabilities as imines. We thus envisaged a similar system of DCL [2] by replacing alkoxylamine B4 with hydrazide B5 to achieve the kinetic switching behavior of the CDNs. The reaction, when performed in a 1: 1: 1 ratio, is very slow with a yield of 21% of A1B4 and 3% of A1B5 after 8 days, indicating that A1B4 is thermodynamically favored over A1B5. When the reaction is done in 2: 1: 1 stoichiometry, it gave a distribution of 17% of A1B4 and 4% A1B5 after 7 days with many unreacted A1. The above two experiment implied that the alkoxyamine B4 also reacted faster than the hydrazide B5 and its product A1B4 is both the kinetic and thermodynamic product compared with A1B5. 2) The kinetic switching of DCL [3] from four constituents generated from four components Finally a third four component DCL [3] was studied in the same conditions as for DCL [1] and DCL [2] above, based on the components A1, A6, B3 and the N-methylbenzohydrazide B5

1) Component selection in competitive experiment

(Scheme 25). The formation of the four constituents A1B3, A1B5, A6B3 and A6B5 was again Interestingly, the initial distribution turned out <1% of the acylhydrazone A1B5 compared to 14% for the corresponding oxime A1B4 in the DCL [2] above, indicating an appreciably lower reactivity of the N-methylbenzohydrazide B5 compared to the alkoxy amine B4. This feature is also reflected in the fact that the evolution of the kinetic traces (Figure 94)

is more gradual than in the previous cases above. This fact that B4 is more reactive than B5 has been proven in the competitive experiment described above (Figure 92).

iv. DCL[4] generated from the four components A1, A4, B3, B5

In order to try if the reactivities of the two aldehydes influence greatly on the switching behavior, the experiment for the set of components A1 + A4 + B3 + B5 with A1 and A4 having similar reactivities were tested (Scheme 26). The differences for A1and A4 is A1 has a methyl group in the 6-position of A4 (6-methyl group of 2-formylpyridine). After 5 minutes, the distribution of the DCL was as follows: A1B3/40%, A4B3/29% together with free A1/10% and free A4/20% both unreacted in the solution (Figure 95). After 96 hours, it reached the equilibrium with a near-statistical distribution for A1B3/19%, A4B3/25%, A1B5/32%, A4B5/21%. The kinetic curve of this experiment is shown in Figure 96. This experiment further proved that the differences of the reactivities of the two aldehydes has a big effect on the switching behavior of the DCLs.

Kinetic switching of CDNs of ligand constituents driven by metal cations of different coordination geometries

The above results demonstrate the time-dependent switching of the CDNs from the kinetic distribution to the thermodynamic distribution driven by the exchange of the kinetically faster imine to the thermodynamically more stable oximes and hydrazones. It was necessary to explore whether the addition of metal cations would induce a similar switching behavior. As is reported in earlier work, [START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Vantomme | Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes[END_REF][START_REF] Men | Higher Order Constitutional Dynamic Networks[END_REF][START_REF] Ayme | Triple Self-Sorting in Constitutional Dynamic Networks: Parallel Generation of Imine-Based CuI, FeII, and ZnII Complexes[END_REF] the presence of metal cations would greatly influence the behavior of a DCL according to the specificity of the metal cation. The adaptation of DCLs in the presence of metal ions were also introduced in Chapter I.

We were thus urged to investigate whether such a switching could also be achieved for a DCL by addition of two different metal cation effectors M1 and M2. Particularly, a CDN underwent switching from the kinetic complex of one metal ion to the thermodynamic complex involving the other metal ion. The achievement of such a switching greatly rely on the difference in both the rate of the ligand formation and relative stabilities of the two generated complexes in the presence of the two metal cations. The evolution of a system undergoing such a CDN switching is represented in Scheme 27. It is crucial to screen the metal cations according to their different properties, i.e. geometry and stability. As already well known, monovalent metal cations M1 such as Ag(I) or Cu(I) favors the formation of tetracoordinated metal complexes with bidentate ligands whereas divalent metal cations M2 such as Zn(II) or Fe(II) prefer to form hexacoordinated octahedral complexes with tridentate ligands. Considering these conditions above, we envisaged to achieve a kinetic switching of the [2 × 2] DCL from a tetrahedral complex of an imine to an octahedral complex of hydrazone upon addition of two metal cations. Accordingly, the kinetic behavior of the DCLs with different combination of the metal ions, as well as organic components, were studied in the presence of two metal cations with respect to the coordination characteristics of the metal cations.

Therefore, we selected pyridyl-aldehydes as one kind of the aldehydes since they can form a bidentate imine ligand upon reaction with an amine component and can also generate a tridentate acylhydrazone or pyridyl-hydrazone ligand when reacting with a corresponding acylhydrazine and pyridyl-hydrazine component. The other aldehyde could be less reactive, without any coordination site. The corresponding aldehyde and amine components adopted in this section are depicted in Scheme 28.

Scheme 28. The structure of the selected aldehydes and amines to set up the [2 x 2] DCLs in the presence of metal cations.

In order to find out the system which could achieve this time-dependent switching, we firstly did the experiments for DCL [5] to DCL [7] with different components by sequential addition of the two metal cations M1 and M2. As such, if the sequential addition of the two metal ions to the [2 × 2] DCL components could achieve the switching from one metal complex of imine to the other metal complex of another hydrazone, this will make it possible for the DCL to attain the switching on simultaneous addition of the two metal cations together with the components within the DCL. Therefore, the three DCLs {DCL [5], [6] and [7]}were tested on sequential addition of two metal cations M1 and M2.

i. DCL[5] generated from the four components A1, A6, B3, B5 in the presence of Cu(I) and Zn(II)

By combining previously reported work [START_REF] Mahata | From 2-Fold Completive to Integrative Self-Sorting: A Five-Component Supramolecular Trapezoid[END_REF] and the switching behavior above for the DCL[3], the imine is the kinetic product which can also act as a bidentate ligand, while the acylhydrazone is the thermodynamic product which can act as a tridentate ligand. Thus, the imine A1B3 should form a tetrahedral complex with Cu(I) or Ag(I), while the acylhydrazone A1B5 should form an octahedral complex with Zn(II) or Fe(II). Therefore, the four components A1, A6, B3, B5 were firstly selected to generate the [2 × 2] DCL in the presence of the two metal cations.

Thus, the DCL [5] was set up from an equimolar A1, A6, B3, B5 (see Figure 97). The two metal cations CuOTf and Zn(OTf)2 were added in sequence. On addition of Cu(I) after 5 minutes, the Cu(I) complex of imine [Cu(A1B3)2] + is almost fully formed with free A6 which does not react due to the lower reactivity.

ii. DCL[6] generated from the four components A2, A5, B3, B5 in the presence of two metal ions

Based on the above result, A1 (6-phenyl-2-formyl pyridine) was replaced by A2 (6methyl-2-formyl pyridine) and A6 was replaced by a less reactive aldehyde A5 to leave enough time for the switching of the complexes as well as inhibit the silver mirror reaction. A series of experiments of combination of the four metal cations were tested for generation of the switching behavior of the DCL [6] from the four components. The DCL [6] of the four components was studied by sequential addition of the two metal salts: first Cu(OTf) or Ag(OTf); then Zn(OTf)2

or Fe(OTf)2.

1) DCL[6]

generated from the four components A2, A5, B3, B5 on sequential addition of Cu(I) and Zn(II)

The DCL [6] was generated from equimolar A2, A5, B3, B5 (Figure 98). Upon addition of Cu(I) after 5 minutes, the Cu(I) complex of imine [Cu(A2B3)2] + already formed in a large amount together with a lot of free A5 and free B5. The spectrum was again a bit broad. On addition of Zn(II) after 5 minutes, the A5B5/23% with the unreacted A5/27%. indicating that the Cu(I) complex of imine still cannot be largely transformed to the Zn(II) complex by replacing the aldehyde A1 with A2. The reason could be due to either the higher stability of the Cu(I) complex of imine or the less coordination ability of the acylhydrazone, which cannot drive the transformation of the Cu(I) complex of imine to Zn(II) complex of acylhydrazone. The key point is to balance these two factors to achieve the switching behavior. According to these results, the DCL [6] with the four components A1 + A5 + B3 + B5 displayed the uncomplete kinetic switching in principle from the pair of kinetic product, the Cu(I) [or Ag(I)] complex of imine A2B3 with another acylhydrazone A5B5, to the other pair of the thermodynamic product, the Zn(II) (or Fe(II))]complex of acylhydrazone A2B5 together with another new imine A5B3. The most probable reason is due to the less coordination ability of the acylhydrazone with Zn(II) or Fe(II) due to the oxygen on the carbonyl of the acylhydrazone. Hence, we envisaged to use a better ligand instead of acylhydrazone to serve as the final ligand for Fe(II) or Zn(II) and also

iii. DCL[7] generated from the four components A2, A5, B2, B3 in the presence of two metals

The above results inspired us to choose a better ligand which is not only thermodynamically more stable than imines but also have better coordination ability than acylhydrazone. The N-methyl pyridylhydrazine B2 was chosen since it can form a tridentate ligand compound with three N coordination sites after reaction with pyridyl-based aldehyde and it is much more stable than imines. The corresponding DCL [7] can be established from its components A2, A5, B2, B3 upon addition of the metal cations. From the previous studies, 98 The same experiment for DCL [7] was also performed with the addition of Ag(I) and Zn(II) in sequence to the mixture of A2, A5, B2, B3. The corresponding 1 H NMR spectra of the evolution can be seen in Figure 103. Similarly, the large amount of [Ag(A2B3)2] + was formed 1 hour after addition of 0.5 equiv. of Ag(I) with the unreacted A5 and B5 in the solution.

The 1 H NMR spectrum became broad 5 minutes after addition of 0.5 equiv. of Zn(II). This is due to the exchange [Ag(A2B3)2] + with Zn(II) since Zn(II) and Ag(I) are both labile metal ions.

At the same time, Zn(II) can also coordinate with B2, resulting in the shift of the peaks of B2.

The separate titration experiment of B2 by Zn(II) is shown in Figure 104. The formation of [Zn(B2)2] + can also be proven by the HRMS-ESI spectrum (Figure 105). After heating at 60°C

for 2 days to reach the equilibrium, the [Ag(A2B3)2] + were largely transformed to [Zn(A2B2)2] + .

However, the agonist compound A5B3 cannot be clearly attributed while the amount of aldehyde A5 decreased. In addition, there is a metallic silver layer on the inner wall of the nmr tube probably due to the silver mirror reaction of the Ag(I) with A5 in the presence of the benzylamine B3 (pka = 9.34). This experiment is of crucial importance for the design of the DCL. It implies that it would be better to choose an appropriate aldehyde which could form the hydrazone much faster than A5 upon reaction with B3, thus avoiding the slow reduction of Ag(I). It is also necessary to choose a less basic amine rather than B3 (benzylamine). It is to be noted that the coordination of the metal cation by the component may influence the kinetic behavior of that component to form its corresponding constituents. In such a case, in a separate experiment, it was found that Zn(II) coordinates pyridyl-hydrazine B2 to give [Zn(B2)2] 2+ . Furthermore, addition of metal cations may catalyze the exchange of components between the ligand constituents and thus accelerate the kinetics of the recombination.

In order to be able to identify the entities present in the rather complicated mixtures, the

1) DCL[8] on simultaneous addition of Ag(I) and Zn(II)

The DCL [8] was thus generated from A2, A8, B1 and B2 and its behavior was studied on simultaneous addition of AgOTf and Zn(OTf)2 (Scheme 29). As seen from the 1 H NMR spectra (Figure 106), 1 hour after addition of the two metal cations, the silver complex [Ag(A2B1)2] + of imine A2B1 was almost fully formed (49%) together with unreacted A6 and B5 due to the slow rate of hydrazone formation. B2 was found to be coordinated with Zn(II).

As the reaction proceeded for 1 day, the zinc complex [Zn(A2B2)2] 2+ appeared and its amount increased with amplifying its agonist constituent A6B4 while the amount of the silver complex

2) DCL[9] on simultaneous addition of Ag(I) and Zn(II)

To verify if the substituents on the pyridyl-aldehyde have any influence on the switching behavior, the DCL [9] was generated from the components A1 (6-phenyl-2-formyl pyridine), A8, B1, B2 (10 mM, 1.0 equiv. each), AgOTf (5 mM, 0.5 equiv.) and Zn(OTf)2 (5 mM, 0.5 equiv.) (Scheme 30). The components were mixed together in CD3CN at room temperature and then were followed by 1 H NMR as a function of time (Figure 109 and Figure 111). After 1 h, the silver complex of imine [Ag(A1B1)2] + formed almost fully together with 48% of unreacted A8 and 50% of B2 as its zinc complex. After left at room temperature for 3 days (or 2 days at In the previous studies, starting from a statistical distribution (about 25% of each of the four constituents) of the initial equilibrated state of the DCL, the maximum amplification achievable for a given constituent was at most twice that in the initial distribution, i.e., from 25%

to a maximum of 50% (together with 50% of its agonist). The processes described here display much larger changes in distributions: they amount to a network switching from an initial state where one pair of diagonally linked agonistic constituents is almost absent to a final state where this same pair is strongly dominant and conversely for the other pair of constituents. For example, in DCL [9], the constituents [Zn(A1B2)2] 2+ and A8B1 are amplified from 1% and 2%, respectively, in the initial kinetic distribution to 41% and 38% in the final thermodynamic distribution, a change by more than a factor of 20.

SUMMARY OF CHAPTER III

To summarize, we studied and controlled the time-dependent switching of the [2 × 2] DCLs from the kinetic distribution of constituents to the thermodynamic one (Scheme 32) either in the absence (section 2A) or in the presence of metal cations(section 2B). Such kinetic switching of the DCLs is achieved by selective screening of the appropriate aldehyde and amino components (amine, hydroxylamine, hydrazine, hydrazide), as well as the metal cations. The determining factors for the screening of the components are as follows:

1) The formation rates usually decrease, and the thermodynamic stabilities increase along the sequence of (aliphatic) imine, acylhydrazone, hydrazone and oxime, leading to the possibility of the generation of the time-depended distributions for a network switching.

2) In the presence of metal cations, it is important to adjust the kinetics of ligand formation for the complex, the thermodynamic stabilities of the two complexes and even the exceptional interaction of the metal cation with the component: a) the formation of the hydrazone-based zinc complex is much slower than the formation of imine-based silver complex, allowing the fast formation of the silver complex of imine; b) the zinc complex of the tridentate hydrazone is thermodynamically more stable than the silver complex of the bidentate imine, which makes possible the exchange of the common component, i.e. pyridyl-aldehyde, from the silver complex of the imine to the zinc complex of the hydrazone; c) The trapping of Zn(II) by coordination with the pyridyl-hydrazine B2 by the formation of [Zn(B2)2] 2+ may slow down the formation of the zinc complex of hydrazone thus allowing the silver complex with the imine constituent to form first.

3) For both cases, in the absence and presence of metal cations, the switching behavior of the DCLs was obtained by simply mixing the components together and following the kinetics

CHAPTER IV. THE C=N FORMATION FOR GENE REGULATION 1. INTRODUCTION

As described in Chapter I, the mechanism of C=N formation consists of nucleophilic attack of amine on the carbonyl group and the removal of water from the tetrahedral intermediate proposed by Jencks in the 1960s. 269 He further indicated that at acidic condition the rate-determining step for C=N formation was the nucleophilic attack of the amine on carbonyl group, while at neutral and basic condition the rate-determining step is the dehydration. 156 Scientists have made great efforts to study and accelerate the kinetics of the imine formation in aqueous phase. [270][271][272][273][274][275] In 1960s Jencks demonstrated both the acid catalysis 156 and nucleophilic catalysis 159 of semicarbazone formation in aqueous phase. Here we are focused on the facilitating of imine formation in aqueous phase to find more application in biological process.

A. Facilitating imine formation in aqueous phase

There are many factors which could influence the imine formation. To facilitate imine formation included both to accelerate the kinetics of imine formation and to increase the yield of imine formation. Considering the two steps of imine formation: the nucleophilic addition of the amine on the carbonyl and elimination of water. From structural factors, the fast-reacting aldehyde would accelerate the nucleophilic addition on the carbonyl which is the ratedetermining step at acidic conditions. To increase the yield of imine formation, both the structural factor and the environment factor would act. They are discussed as follows.

i. The fast-reacting aldehyde for imine formation

Jencks and co-workers pointed out that the o-substituted aryl aldehyde reacted somehow more rapidly than p-substituted aldehyde with methoxy, hydroxy, chloride and nitro groups. 276 Similar phenomenon was found by Wang and Li for the reaction of ortho-halobenzaldehyde derivatives with peptides especially o-chloro benzaldehyde. 277 Bane and coworkers reported on the findings of the o-phosphate group of the aryl aldehyde strongly accelerates the kinetics of hydrazone formation through the intramolecular general acid catalysis. 278 Moreover, Gillingham and co-workers demonstrated the fast formation of oxime from phthaldehyde through the generation of the intermediate cyclic hemiaminal. 279 They also introduced a boronic acid group in the ortho position of benzaldehyde, which in the first step participated in the formation of the tetrahedral intermediate very rapidly. 262 Kool and co-workers systematically studied the structure effect on the reactivity of aldehyde with acylhydrazines. 127 They found that: 1) the electron-deficient carbonyl groups react much faster on average; 2) steric hindrance plays moderate to small effect on hydrazone formation; 3) alkyl aldehydes react mmuch faster than aryl ones; 4) aldehydes with nearby basic group (such as 2-formyl pyridine) react much rapidly due probably to the internal acid-base catalysis.

Pyridoxal phosphate (PLP), as a co-enzyme in the transamination reactions, can form an internal aldimine with the ε-amino group of a specific lysine group of the aminotransferase enzyme. [280][281][282] The transamination includes three steps (Scheme Because PLP has four functional groups, it can exist in different protonation and tautomer states in water. 283,270 Therefore, the imine formation from PLP and amino acids in aqueous media have been widely studied 274,[284][285][286][287][288] such as PLP with hexylamine 289 and dodecylamine 273,290 as well as amino acids. 154,[291][292][293][294] Chan-Huot and Limbach studied the protonated states of PLP, 295 the pH dependence of aldimine formation from PLP and 15 Nlabelled diaminopropane, [START_REF] Brady | Thermodynamically-Controlled Cyclisation and Interconversion of Oligocholates: Metal Ion Templated "living" Macrolactonisation[END_REF] N-α-labelled L-lysine, [START_REF] Brady | Thermodynamically-Controlled Cyclisation and Interconversion of Oligocholates: Metal Ion Templated "living" Macrolactonisation[END_REF] N-ε-labelled L-lysine, 286 hydrogen bonds of PLP in polar solution, 296,297 and the stability, protonation and tautomer states of the aldimine. 298 They found that: 1) only the free aldehyde and the hydrate forms existed at low pH;

2) all of the protonated species were present at neutral conditions; and 3) the zwitterionic form was favored before deprotonation at high pH. These studies provided the possibilities to tune the imine formation through changing the protonation states.

Hinz and co-workers studied the kinetics and thermodynamics of imine formation from pyridoxal phosphate (PLP) and pyridoxal (PAL) with 6-aminocaproic acid and L-serine (Scheme 34). 299 They found that the reaction rate increased with the increasing of the pH of PLP reaction with 6-aminocaproic acid due to the decrease of the activation energy. This was because the rate-determining step under the studied pH (6.6-8) was the attack of the deprotonated amino acids on the carbonyl. While for PAL reaction with 6-aminocaproic acid, the activation energy was much higher. This is because for PAL, there was the equilibrium between free aldehyde and the cyclic hemiacetal formed. Therefore, the activation energy also required the dissociation of the hemiacetal to generate the free aldehyde. In addition, the phosphate group played an important role in preventing the hemiacetal formation. This experiment indicated that PLP had much faster and low activation energy for imine formation with amino acids. Similar results were obtained by the work of Blanco and co-workers 270 , in which they indicated PLP has the largest rate constant for imine formation and the lowest constants for imine hydrolysis. In addition, the role of pyridine nitrogen in pyridoxal phosphate was also studied by Grisword and Toney. 300 By selectively adjusting the protonation states of pyridine nitrogen, the electrophilic strength of PLP could be modulated to increase the desired product while decrease the unwanted side product.

Scheme 34. Representation of the structures of the PLP, PAL, 6-aminocaproic acid and L-serine.

ii. The increased yield of imine formation

Systematic studies of the influence of structural factors as well as the external effectors on imine formation in aqueous solution, however, have been less frequent. 301 While accelerating the kinetics of C=N formation, it is challenging to increase the yield of imine formation since it is a reversible reaction and the presence of water would always induce the hydrolysis of the imine.

Godoy-Alcántar and Lehn 302 studied structure-stability correlations for imine formation from 25 aldehydes and 13 primary amines in water (Figure 116A). The involvement of considerable amounts of hydrated species for pyridyl aldehydes and most aliphatic aldehydes was taken as an indication that these should be the most reactive carbonyl compounds. The reactions of imine formation were carried out in three different buffers of pD 7.5 (D3PO4 + NaOD), pD 8.5 (ND4OD + DCl) and pD 11 (NaHCO3 + NaOD), separately. To obtain high yield of imine an excess of amines was needed. From these observations, a three-parameter linear equation correlating the logarithms of imine formation constants with pKa values and HOMO energies of the amines and LUMO energies of the aldehydes was obtained (Figure 116B). This is particularly useful for the study of imine formation and exchange as well as for the construction of dynamic covalent libraries. found to be the anion recognition properties of the km which lead to the high yield of imine formation. The titration of PLP by km at pH 7 and the pH dependence of imine km-PLP formation showed that the imine formation required only 1 equivalent of km to reach full formation of imine only in the range of pH 7.0-8.7. The reasons were i) the complete protonation occurred at acidic pH; ii) the imine formation was not complete at higher pH because km was almost neutral in these conditions and didn't have any attractive effect for PLP; iii) km provided an ionic environment through the charges of the amine groups at pH 7.0-8.7, which can organize together to stabilize the generated imine and offered a hydrophobic surface to prevent the imine hydrolysis. Another method of dynamic modifications of amines in water with high yields is the aminal formation. Kovaříček and Lehn 130 studied the reactions of aldehydes and amines (primary amines and secondary amines) (Scheme 35). The salicylaldehyde reacted with isopentylamine to generate imine driven by the hydrogen bond formation. While pyridine aldehyde reacted with N,N'-dimethyl-1,3-diaminopropane, it generated a six-member-ring aminal. Interestingly, by introducing the carboxylic group in the alpha position of benzaldehyde, a five or six member-ring amino-lactone was generated from reacting with piperidine. This work prompt us to make multi-functional aldehyde with OH or carboxyl group in the alpha position in the 2-carbonyl-pyridine, which would also be a good candidate to achieve a higher yield of conversion. This example demonstrates that by changing the microenvironment of the reaction in aqueous phase, the imine formation can be enhanced, which offers a new way to increase the efficiency of this dynamic reaction. The above strategy indicated that it is promising to find or make the aldehydes which could have high yields of imine formation. Considering the multiple application of imine formation from PLP and amino acids in enzymatic reactions in biology, we were curious if the formation and breaking of imine bond from the aldehyde and lysines could realize the reversible regulation of genes since histones are abundant in lysine. The details of the introduction histones and its modification as well as gene regulation are as follows.

B. Histones modifications i. The structure of histone and nucleosome

Histones are highly basic proteins in eukaryotic cell nuclei which play a crucial role in packing the DNA molecule in an orderly way into the highly ordered structure unitnucleosome (Figure 119A). They are relatively small proteins with a very high ratio of positively charged amino acids, mainly lysine and arginine.

There are five types of histones in humans are:H1/H5, H2A, H2B, H3, and H4. Among them, histones H2A, H2B, H3 and H4 are known as the core histones or nucleosomes histones, while histones H1/H5 are the linker histones (Figure 119B). The core histones all exist as dimers. The four distinct dimers then come together to form one octameric nucleosome core.

H1 is involved with the packing of the "beads on a string" sub-structures into a high order structure, and its details have not yet been solved. Histones are the main structural proteins of chromatin and play an important role in regulation of gene expression. In 1974, the major progress came in understanding the structure of chromatin structure with the discovery of the fundamental packing unit known as the nucleosome, which gives a beads-on-a-string appearance in electron micrographs taken after the treatments that unfold higher-order packing. The DNA string can be broken into nucleosome beads by digestion with enzymes that degrade DNA (deoxyribonuclease). After the digestion, only the DNA between the nucleosome beads is degraded. The rest remain as double helix fragments 146 nucleotide pairs long bound to a specific complex of eight nucleosomal histones (the histone octamer).

The crystal structure of the nucleosome was obtained in 1997 by Richmond. 305,306 The core histones are among the most highly conserved of all known proteins. This

ii. Gene regulation-acetylation and deacetylation

Generally, gene expression is the process where information from a gene is used in the synthesis of a functional gene product. The products are proteins in most cases, whereas in nonprotein-coding genes, it is a functional RNA. Virtually the regulation can occur in any step of the gene expression including the transcription, RNA splicing, translation, and posttranslational modification of a protein. Thus, it is very important for all the living organisms as it increases the versatility and adaptability of an organism by allowing the cell to express protein when needed. This is of great importance for the evolution of the species.

One of the strategies is to alter the chromatin structure of DNA by modification of its histones. The free N-terminal of lysine and arginine in histones can be modified in various ways such as methylation, acetylation, phosphorylation, ubiquitination and other modification processes under the action of related enzymes. Among these processes, the methylation of histone modification is the most stable method, so it is most suitable for stable epigenetic information. The acetylation modification is a highly dynamic process, and the others are unstable modifications. Through the modification of histone, the affinity of histones and DNA double-strands can be affected, thereby changing the looseness or agglutination state of chromatin, or affecting the affinity of other transcription factors and structural gene promoters to play a role in gene regulation. Herein, we are mainly interested in the acetylation of histones to influence the gene expression due to the highly dynamic feature.

The discovery of the fact that acetylation of histones caused changes in the transcription activity dated back to the work of Allfrey and co-workers in 1964. 307,308 Acetylation and deacetylation are the processes in which the N-terminus tail of lysine protruding out from the chromatin are acetylated and deacetylated under the corresponding enzymes histone acetyltransferase (HATs) and histone deacetylase (HDACs) (Figure 120). Many diseases were found to be relevant to the acetylation of the lysines in histones such as inflammatory lung diseases. For example, in asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy.

Therefore, we are interested to see whether a simple imine formation with N-terminus of lysines in histones could generate reversible control of gene expression. Therefore, it is of great importance to search for the aldehyde which could form high yield of imine in aqueous phase.

In this part of the present work, we envisage to generate the imines with high yields in aqueous phase. The factors of the reactivities of aldehydes, hydrophobic environment of the reaction (here mainly the hydrophobicity of amines) as well as the medium acidity were investigated. The imine formation from a series of aldehydes and amines was explored especially with the derivatives of lysine. Considering the abundance of lysine in histones, we further studied the imine formation from an aldehyde and a poly-lysine such as tri-lysine as a model for modification of histones, which might give us the possibility to regulate the gene expression with dynamic covalent reactions.

RESULTS AND DISCUSSIONS

Screening of the substrates i. Fast-reacting aldehydes

Combining the factors discussed above with the good solubility in aqueous phase, some aldehydes were chosen to find the one which could generate the product (such as imine, aminal or lactone) with the highest yield in aqueous phase (Scheme 36).

The selected aldehydes were mainly of three types: 1) pyridyl-aldehyde derivatives, which have basic pyridine nitrogen and have been proven to have higher reactivity; 2) electrondeficient aldehydes which have higher reactivities; 3) o-substituted aldehydes which showed higher reactivities before. The imine formation of the aldehydes and N-α-acetyl lysine were studied in aqueous phase at different pH. The corresponding yields of imine formation is shown in Table 10.

Scheme 36. The structures of the aldehydes tested for imine formation in aqueous phase.

As seen from Table 4, most of the aldehyde can form hydrates in different buffers except DSBAL (entry 8). In addition, the imine formed in a very low yield (less than 10%) at lower pH (pH 7.4 and pH 8.1) due to the protonation of the ε-amino group in the N-α acetyl lysine.

With the increase of pH to 11, the yield of imine increased and the amount of the free aldehyde (or the free amine) as well as the aldehyde hydrates decreased. Among all the tested aldehydes, PLP formed imine with the highest yield (up to nearly 70%) at basic condition (entry 1, pH = 11.0). There are two reasons for this: i) the pyridine nitrogen activate the carbonyl group and makes it a fast-reacting aldehyde; ii) the ortho-hydroxy group could stabilize the imine through the formation of the intramolecular hydrogen bond.

In comparison with PLP, other aldehydes have much lower yield of imine formation.

The DSBAL yielded 56% of imine which is a bit less than PLP but much better than the rest of the aldehydes (entry 2). It is due to the two electron-withdrawing groups, which greatly activated the carbonyl group. Similarly, the ortho-sulfonate substituted aldehyde OSBAL also generated a comparable 51% imine compare to DSBAL (entries 2 and 3). Moreover, SFAL formed 49% of imine. For the three pyridyl aldehydes, the yields of imine are 46%, 44% and 37% for 2, 3 and 4-pyridinecarboxaldehydes, respectively. This means that introducing the electron-deficient group in the ortho and para-position plays a more important role than meta position.

The above experiments indicated that the aldehyde with electron-deficient group produced imines in the yield range of 17% to 69% at pH 11. Due to the existence of hydrolysis, which competed with imine formation, it is important to develop reactive aldehyde which can also stabilize the generated imine by more interactions like hydrogen bonding through introduction of other substituents.

_ [a] _ [a] 17% Hydration _ [a] _ [a] _ [a]
[a] _ represents no imine or hydration was found. n.d. not determined. From the table, only in basic condition the imine formation is good because the N-α-acetyl lysine has free amino group. We draw a conclusion of the reactivity among the different aldehyde:

ii.

Hydrophobic effect of the amines

Along with the reactivities of the aldehydes, the properties of the amines could also influence the imine formation. As mentioned earlier, hydrophobic effect are very important driving force in biological processes such as protein folding. 309 As such, they are always used to adjust the self-assembly behavior of the supramolecular polymers. 310 Inspired also by the enhanced imine formation through the addition of double-stranded DNA, 304 we were curious to know if introducing of amines with more hydrophobic substituents would yield imines efficiently through the hydrophobic interactions in aqueous phase. Therefore, the following aliphatic amines with different size of hydrophobic groups were selected to study the imine formation with PLP in aqueous phase (Scheme 37). The experiments were conducted in phosphate buffer at pH 8 at the final concentration of 5 mM.

Scheme 37. The structures of the amines with hydrophobic groups tested for imine formation in aqueous phase.

As seen from Table 11, the yield of imine increased with the size of the hydrophobic group on the amine. For n-butylamine, the yield of imine was 39% together with 29% of unreacted aldehyde and hydrate of PLP. The benzylamine yielded 55% of imine. 1naphthylmethylamine resulted, in 64% of imine product in the same condition. The tryptamine didn't generate higher yield probably due to the Pictet-Spengler reaction, to form the cyclic product (Scheme 38). These results indicated that the hydrophobic effect indeed influenced the yield of imine formation in aqueous phase through decreasing the concentration of water by creating a relative hydrophobic environment for the reactants. The more hydrophobic groups included in the reactants, the higher yield of imine was generated. [a] The experiment of imine formation from equimolar PLP and amine in phosphate buffer at pH 8. n.d. not determined.

Scheme 38.

The mechanism of the Pictet-Spengler reaction from a β-arylenylamine and an aldehyde or ketone to form a tetrahydroisoquinoline in the presence of acid catalysis. 311

iii. pH dependence

For imine formation in aqueous phase, pH is another important factor. There are several points to be noted: a) an acid could protonate the carbonyl group of the aldehyde, which would activate the carbonyl and make it a better electrophile; b) an acid could also protonate the amine, making them non-nucleophilic any more, which would inhibit the its addition to the carbonyl.

Thus, the following fast-reacting aldehydes were selected to find the best pH range for imine formation with N-α acetyl lysine in water (Scheme 39). The pH titration curves for the imine formation from different aldehydes and N-α acetyl lysine were shown in Figure 122.

Scheme 39. The structures of the aldehydes for imine formation in aqueous phase. As seen in Figure 123, no imine is formed at pH 3.6 and only the free aldehyde and the hydrate of the aldehyde were observed, which was the same as reported by Limbarch and coworkers. 297 This is because the amine is fully protonated at this pH. By increasing the pH to 6.2, the hydrate of PLP decreased with the appearance of the imine peak at around 9 ppm. The yield of imine increased with the increase of the pH. This is because the amine was less protonated when the pH was increased. Moreover, for PLP, the pyridine nitrogen was protonated, which makes the electron-withdrawing properties even stronger. When the pH was further increased to 10.5, the imine reached the highest yield of 65% with almost no hydrate observed. On continuously increasing the pH, the yield of imine decreased. This could be due to the difficulty of the protonation of the carbonyl group at higher pH. And also, the phenol group was deprotonated, making PLP more electron-rich, resulting its low reactivity. When using a simple 4-pyridinecarboxyaldehyde (PPAL) (Figure 124), there are only the signals of free aldehyde (50%) and hydrate of aldehyde (50%) below pH 7.8. On increasing the pH to 8.9, the signal of imine was observed. The yield of imine continuously with the increase of pH. The imine was almost fully formed at pH 12.1. The use of 2-pyridine-carboxyaldehyde (OPAL) displayed the similar behavior here where it presented a bit higher yield of imine under the same conditions, which can be seen in Figure 125. For CAXAL, the imine signal was detected clearly at pH 10.3, but no imine was detected at lower pH. Like the above experiments, the yield of imine increased with the increase of pH.

The yield of imine reached 45% at pH 12.1 (Figure 126).

CAXAL CAXAL-L1

For a derivative of salicylaldehyde (ASAL), the imine signal was detected at pH 6.6 and no hydrate was observed. The yield of imine also increased with the increase of pH 6.6 to 10.3 in a gradual trend. When pH was above 10.3, the yield of imine decreased due probably to the deprotonation of the hydroxy group, thus the imine cannot be stabilized by the hydrogen bonding. Therefore, the amount of the imine decreased. The evolution of this 1 H NMR spectra was shown in Figure 127. Finally, the aldehyde bearing both the carboxyl group and hydroxy group (SAXAL) in the ortho position was chosen to study the imine formation. As seen in Figure 128, there wasn't imine formed at pH 6.3 due to the full protonation of the amine at this pH. The imine signal appeared at pH 7.3 and kept increasing with the increasing of the basicity of the solution. The amount of imine reached its maximum (57%) at pH 10.1. Thereafter, the yield of imine declined with the increase of pH. The reason could be the less stability of the formed imine due to the disappearance of the hydrogen bonding from the hydroxy group at highly basic conditions. From the above experiments, the yield of imine differs depending on the pH of the aqueous medium. The corresponding pH titration curves for the reaction of imine formation from the aldehydes and N-α acetyl lysine are shown in Scheme 15 above. For the tested aldehydes, the best range for the efficient imine formation is between 10 to 11. Th reason lies in the fact that the pKa of the ε-amino group of the N-α acetyl lysine is about 10.5. At pH below 10.5, there are always some amines protonated which cannot react with the aldehyde, leading to the lower yield of imines. While at higher pH above 11, the ortho hydroxy group of some aldehydes has lower yield of imine due to the deprotonation of the hydroxy group at these conditions, resulting in the disappearance of the hydrogen bonding. In addition, the deprotonated hydroxy group served as the electro-donating group, which decreased the reactivity of the aldehyde.

Imine formation driven between PLP and Lysine derivatives

From the above experiments, PLP is the aldehyde which could generate the higher yield of imine at pH between 10 and 11. Therefore, it was chosen to test the imine formation with

i. PLP reacting with mono substituted Lysine

The imine formation from PLP and L1 was firstly studied and followed by the 1 H NMR spectroscopy (Figure 129). It was found that the imine formed very fast from PLP and L1. For N-ε-acetyl-lysine (L2), the similar experiment was conducted in the ratio of 1 : 1 ratio, the amount of PLP decreased to 45% after 5 minute with the appearing of the imine signal at 7.6 ppm which took up 55%. After 1 hour, there is still 34% of free PLP left unreacted. The final yield of the imine PLP-L2 was 66%. The kinetic curve is shown in Figure 130B. In the following, the experiment was conducted for the reaction of PLP with lysine (L3) (with both α-amino and ε-amino groups) in the ratios of 1:1, 2:1 and 4:1 to generate the full conversion of lysine to the imine product.

As seen in Figure 132, the PLP and L3 were mixed in the ratio of 1:1 in phosphate buffer (pH = 11.0) at 25℃. After 20 minutes, the reaction reached the equilibrium. Lysine has two types of amino groups: α-amino and ε-amino groups. It could generate three imines with four imine peaks on reacting with PLP: mono imine PLP-α-L1, mono imine PLP-ε-L1 and the bisimine PLP-α,ε-L3. The composition of the imines did not change after 20 minutes. The final composition of the reaction mixture/outcome was 47% PLP, 33% PLP-ε-L3, 10% PLPα-L3 and 4% of bisimine product PLP-α,ε-L3 with 2% of hydrate of PLP. The higher yield of PLP-ε-L3 in comparison with PLP-α-L3 is due to the higher pKa of ε-amino (pKa = 10.5) than α-amino of lysine (pKa = 9.0). The total amount of imine formed added up to about 51% including the two mono imines and the bisimine together. While the experiment of PLP with L3 in the ratio of 4:1 (Figure 134), it resulted in the final distribution of the mixture: 22% PLP-ε-L3, 40% PLP-α-L3 and 19% of bisimine product PLP-α,ε-L3 together with the access of free aldehyde PLP and its hydrate. The total amount of imine added up to 81% considering the conversion of the amino groups of L3.

ii. PLP reacting with tri-lysine and penta-lysine

To mimic the reaction between histones (abundant in lysines) and PLP, the imine formation from the polylysine and PLP was firstly investigated in different ratios. Therefore, the tri-lysine KKK (L4) were used to study the imine formation under the same condition. The experiments were also conducted in different ratios to get higher conversion of the amino groups to imines.

As seen in Figure 135, on mixing the equal amount of PLP and L4, a series of imine peaks were observed at around 9 ppm due to the presence of many species as there are 3 εamino and 1 α-amino groups within one L4, which can generate different monoamine, bisimine, tris-imine and tetra-imine products. The total yield of amine conversion was about 57%.

PLP PLP-ε-L3 PLP-α-L3

PLP-α, ε-L3 hydrate Therefore, by using 3 equivalents or 4 equivalents of PLP, a similar yield of imine was obtained.

The current results indicated that PLP gave higher yield of imine up to 83% with polylysine in the presence of 3 equiv. of PLP. The reason could also be due to the presence of the hydrophobic effect from the alkyl chain of the polylysine. Thus, it becomes very interesting for the further investigation of imine formation from PLP and L5 as well as the histones which are abundant in lysine and play important roles in the process of gene expression.

SUMMARY OF CHAPTER IV

In this chapter, we investigated the yield of imine formation in aqueous phase influenced by several factors. The results have shown that the reactivity of the aldehydes, the hydrophobic effect of reactants as well as the pH could greatly influence the yield of imine formation. It was found that the aldehyde which generated higher yield of imine included not only the electronwithdrawing group to activate the aldehyde, but also the ortho-substituent to stabilize the generated imine. The selected PLP, which is a co-enzyme of the transamination reactions, have shown higher yield of imine formation up to 84% with KKK at basic pH conditions.

Further studies will be oriented to determine the imine formation of PLP with oligolysine such as KKKKK and histones. The exploration of more reversible chemical reactions which could convert amino groups of lysine to a new product in a higher yield will also be continued, especially for those products which can be formed stable at physiological conditions.

CHAPTER V. CONCLUSION AND PERSPECTIVES

This thesis was based on dynamic combinatorial chemistry of imine bonds and used them to study different adaptive behaviors from a kinetic and thermodynamic point of view, including the catalysis of imine and hydrazone formation (Chapter II), CDNs switches in organic phase and their out-of-equilibrium states (Chapter III). In addition, from a thermodynamic point of view, the imine formation in aqueous phase was studied to achieve the increased yield of imine formation for potential application in gene regulation though modification of histones.

In the first chapter, we gave a general introduction of the development from supramolecular chemistry to constitutional dynamic chemistry, the adaptive behavior of CDLs as well as the dynamic imine chemistry used in CDLs.

In the second Chapter, we have demonstrated the acceleration of the imine and hydrazone formation by the addition of metal salts such as Ag (I) and Zn (II). The simultaneous addition of metal salt and auxiliary amine resulted in remarkably faster formation of the hydrazone complex. By adding three catalysts, the dynamic system evolves from the formation of the kinetic product (the silver complex of imine) to a thermodynamic product (the zinc complex of hydrazone), and this prompted us to examine kinetic switching behavior of CDLs.

In the third Chapter, we used the dynamic imine formation to establish CDNs [2 × 2] and its associated CDLs and applied the kinetic switching behavior of the second chapter into DCLs, thus realizing a time-dependent network switching from a kinetic distribution to a thermodynamic distribution both in the absence and presence of metal cations.

Finally, in the fourth Chapter, from the thermodynamic point of view, we discovered the rapid and quantitative formation of imine from different aldehydes and lysine derivatives in a phosphate buffer, indicating that pyridoxal phosphate has much higher yield of imine formation in basic pH 10-11. This gives it great potential for use in certain applications such as the modification of proteins in biology.

To sum up, in the present work, we have broadened our knowledge and understanding of the CDC of imines, in particular from the kinetic point of view, which has long been neglected. Understanding the influence of structural effects on kinetic and thermodynamic behavior opens the way to the establishment of complex multiphase systems to generate faster and simpler production in adaptive chemistry. In addition, these studies have indicated potential applications in biological activities such as protein modification to regulate gene expression.

CHAPTER VI. EXPERIMENTAL PART 1. GENERAL PROCEDURES

Solvents and Chemicals

All the reagents and solvents were purchased from Sigma-Aldrich, Alfa Aesar,

Methods and Instruments

i. Chromatography Methods

Thin Layer Chromatography was performed using silica on TCL Aluminium foils (silica gel matrix with fluorescent indicator 254 nm, thickness: 500 μm, sigma-Aldrich). The visual detection of the TLC was performed using UV-lamp and iodine vapor. The flash column chromatography was performed using silica gel (60Å, 230-400 mesh, 40-63 μm, Sigma-Aldrich). The reverse phase column (C18 column) was performed with a water/CH3CN gradient as the eluent.

ii. Nuclear Magnetic Resonance Spectroscopy

NMR spectra were recorded on Bruker Avance III plus 400 (400 MHz for 1 H and 100

MHz for 13 C) and Bruker Ascend Spectroscope Avance Neo-500 MHz (500 MHz for 1 H and 125 MHz for 13 C). All the collected spectra using CD3CN as the solvent were referenced on residual CD3CN signal as 1.94 ppm, others were referenced on residual solvent signal according (pentane: CH2Cl2 = 2:1). (m, 3H).

General methods for preparation of imines and hydrazones

Aryl aldehydes Ax (1 equiv.) and 4 Å MS were added to ethanol solutions of amines, hydrazines By (1 equiv.) respectively. After the mixtures were heated under reflux for 6 hours, the mixture was filtrated to remove 4 Å MS and washed by CH2Cl2 (20 mL) The solution was then dried with Na2SO4. After evaporation of the volatile materials under reduced pressure, the desired imines were afforded in a quantitative yield. Purer imine products could be obtained via vacuum distillation. all of the relevant imines and hydrazones were reported before. The characterizations were consistent with the literature values.

General methods for preparation of the relative complexes 0.5 equiv. of metal ions were added to the CD3CN solutions of 1 equiv. of the ligand constituents. The mixtures were heated overnight at 70 °C. The complexes were always freshly prepared prior to every new experiment. The complexes were never isolated, all the present experiments and analysis were done in CD3CN solution. Nevertheless, all of the relevant imines, hydrazones and complexes were reported before. The characterizations were consistent with the literature values. [1]

General methods for imine and hydrazone formation in the absence of metal salts

In a typical experiment, the stock solution of aryl aldehydes Ax (60 mM), the amine or hydrazine By (60 mM) and the internal standard (hexamethyldisiloxane, 33.3 mM) was prepared in advance. And then the same volume (100 μL) of Ax and By were mixed together with addition of internal standard (10 μL) in CD3CN (600 μL). After vigorous shaking, the resulting mixture was monitored at 25°C by 1 H NMR as a function of time.

General methods for imine and hydrazone formation in the presence of metal salts

In a typical experiment, the stock solution of aryl aldehydes Ax (60 mM), the amine or hydrazine By (60 mM), metal salt (60 mM) and the internal standard (hexamethyldisiloxane, 33.3 mM) was prepared in advance. And then the same volume (100 μL) of Ax and By were mixed together with 50 μL metal salt (or 5 uL for catalysis experiment) and the internal standard (10 μL) in CD3CN (600 μL). After vigorous shaking, the resulting mixture was monitored at 25°C by 1 H NMR as a function of time.

General methods for hydrazone formation in presence of B1 or metal salts

In a typical experiment, the stock solution of aryl aldehydes Ax (60 mM), hydrazine B2

General methods for hydrazone formation in presence of both B1 and metal salts

In a typical experiment, the stock solution of aryl aldehydes Ax (60 mM), the amine B1 (60 mM), hydrazine B2 (60 mM), metal salt (60 mM) and the internal standard (hexamethyldisiloxane, 33.3 mM) was prepared in advance. And then the same volume (100 μL) of Ax, B2 and B1 (or 5 uL for catalysis experiment) were mixed together with 50 μL metal salt (or 5 uL for catalysis experiment) and the internal standard (10 μL) in CD3CN (600 μL).

After vigorous shaking, the resulting mixture was monitored at 25°C by 1 H NMR as a function of time.

General methods for hydrazone formation in presence of catalytical amount of acid or metal salts

In a typical experiment, the stock solution of aryl aldehydes Ax (60 mM), the amine B1 7.39-7.35 (m, 2H, H 8,8' , 7.01-6.97 (m, 2H, H 9,9' ), 3.82 (s, 3H, H 11 ); [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR (126 MHz, CD3CN): δ 160.06 (C 10 ), 157.05 (C 6 ), 156.79 (C 5 ), 143.65 (C 7 ), 142.05 (C 1 ), 140.39 (C 3 ), 129.96 (C 4 ), 123.66 (C 8,8' ), 120.82 (C 2 ), 115.12 (C 9,9' ), 55.87 (C 11 C, 49.50; H, 3.81; Br, 27.44; N, 19.24; found: C, 49.44; H, 3.86; N, 19.18. ), 6.97 (t, J = 10.0 Hz, 1.0 Hz, 1H, H 1 ), 6.61-6.35 (m, 2H, H 3,3' ), 3.57 (s, 3H, H 11 ); [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR (126 MHz, CD3CN): δ161.05 (C 5 ), 151.92 (C 12 ), 148.53 (C 9 ), 146.02 (C 16 ), 142.95 (C 14 ), 141.84 (C 7 ), 139.06 (C 4 ), 133.22 (C 10 ), 130.51 (C 1 ), 129.12 (C 2,2' ), 128.23 (C 3,3' ), 128.19 (C 6 ), 126.42 (C 8 ), 119.73 (C 15 ), 110.50 (C 13 ), 33.42 (C 11 7.55-7.45 (m, 2H, H 9,9' ), 6.99-6.86 (m, 2H, H 10,10' ), 3.78 (s, 3H, H 12 ), 2.54 (s, 3H, H 1 ); [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR (126 MHz, CD3CN): δ 161.02 (C 11 ), 160.13 (C 2 ), 156.96 (C 7 ), 150.17 (C 6 ), 140.78 (C 8 ), 140.27 (C 4 ), 128.41 (C 3 ), 127.00 (C 5 ), 124.80 (C 9,9' ), 115.40 (C 10,10' ), 55.98 (C 12 ), 26.47 (C 1 ). ESI-MS: calculated for

[C28H28N4O2+Ag] + 559.1258, found: 559.1254. 7.63-7.48 (m, 2H, H 8,8' ), 7.06-6.91 (m, 2H, H 9,9' ), 3.81 (s, 3H, H 11 ); [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] 8,8' ), 115.45 (C 9,9' ), 56.03 (C 11 ); ESI-MS: calculated for [C26H22Br2N4O2+Ag] + 686.9155, found: 686.9153. Where catalytic effects are large, k1 may be considered negligible and rate measurements on the catalysed reaction can therefore provide k2 (and k3) directly. However, this is not necessarily the case and if, for example, a rate acceleration by a factor of 5 were to be observed under catalysis, then kobs = k1 + k2 = 5k1 and thus k2 = 4k1.

For a reaction where two catalysts are effective and have been studied separately so that k2 and k3 are known, the value of the observed rate constant when both catalysts are present in the reaction mixture should be k'obs = (k1 + k2 + k3) if there is NO synergy between the catalysts.

If there is a positive synergy, then k'obs should be greater than this sum.

In a practical sense, catalyst synergy is a useful phenomenon but whether the simple analysis above can be applied to metal ion and amine catalysis of imine and hydrazone formation seems unlikely, since its basic premise that the catalyst concentration is constant cannot hold. If, for example, it is assumed that Zn(OTf)2 dissolves in CH3CN to give [Zn(NCCH3)6] 2+ and that on addition of pyridine-2-aldehyde and anisidine, this extremely labile cation is chelated to a small degree by the aldehyde in a "pre-equilibrium" to give the activated species with carbonyl-O bound to Zn(II) which then undergoes rate-determining nucleophilic attack by the amine to give an addition product that very rapidly undergoes elimination to the imine, I, then the rate of the reaction would be given by RI=k given above where C = [Zn(NCCH3)6] 2+ remains at an essentially constant concentration provided the chelation equilibrium is very unfavorable, so that the observed kinetics would be that of a simple second-order reaction. Note that the Zn(II) could also coordinate the amine but this would be less extensive than that of the aldehyde (since there is no chelation) and in any case would inhibit reaction because the bound amine is not nucleophilic. A real complication arises from the fact that the product imine is a good chelating agent, so that, as seen by NMR spectroscopy, the Zn(II) is ultimately bound to this ligand and not to CH3CN. Whether or not [Zn(imine)(CH3CN)2] 2+ (which presumably would form during the early stages of the reaction where the zinc concentration would be much greater than that of the imine) or [Zn(imine)2] 2+ could bind and activate the aldehyde and therefore act as catalysts themselves, the catalyst concentration must vary and at most it might be argued that the rate law R = k[Ax][By] [C] could provide an approximate treatment of the initial stages of reaction.

For easy comparison of the initial rate constant, the corresponding rate constants were calculated from a fit to a second-order reaction rate equation (1/[At] = 1/[A0] + kt) over the initial 10% of the product (t10). In some cases, it was calculated from integration of the first 1 H NMR spectrum as the yield of the product is already above 10%.

i. The kinetics of imine formation in the absence of presence of metal salts

1) Kinetics of A1 + B1 in absence of metal salts 2) Kinetics of A1 + B1 in presence of AgOTf 3) Kinetics of A1 + B2 in presence of Zn(OTf)2 2) Kinetics of A1 + B2 in presence of both B1 and AgOTf The solution was then dried with Na2SO4. After evaporation of the volatile materials under reduced pressure, the desired imines were afforded in a quantitative yield. Purer imine products could be obtained via vacuum distillation.

General methods for preparation of oximes 3

Pyridine (1.1 equiv.) was added dropwise to a stirred solution of o-benzylhydroxylamine hydrochloride (1.3 equiv.) and aldehyde (1.0 equiv.) in methanol or ethanol (4 mL/mmol) and the mixture was heated at reflux for 4 h. The solvent was removed under reduced pressure, and the remaining solid residue was dissolved in CH2Cl2 (20 mL/mmol) and washed with water (20 mL/mmol). The aqueous layer was extracted with CH2Cl2 (20 mL/mmol×3) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography.

General procedure for preparation of the relevant complexes:

0.5 equiv. of metal salt were added to the CD3CN solutions of 1 equiv. of the ligand constituents. The complexes were always freshly prepared prior to every new experiment. The complexes were never isolated, all the present experiments and analysis were done in CD3CN solution. Nevertheless, several relevant components, constituents and complexes were reported before; the characterizations were consistent with the literature values. [4][5][START_REF] Dietrich | Diaza-Polyoxa-Macrocycles et Macrobicycles[END_REF][7][START_REF] Cram | International Edition in English[END_REF][START_REF] Lehn | Supramolecular Chemistry-Scope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture)[END_REF][START_REF] Ma | Biomedical Applications of Supramolecular Systems Based on Host-Guest Interactions[END_REF][START_REF] Hoeben | About Supramolecular Assemblies of π-Conjugated Systems[END_REF][START_REF] Osypenko | Supramolecular Self-assemblies of Triarylamines: Fundamental Studies and Applications[END_REF][START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF][START_REF] Kramer | Self-recognition in Helicate Self-assembly: Spontaneous Formation of Helical Metal Complexes from Mixtures of Ligands and Metal Ions[END_REF][START_REF] Brady | Thermodynamically-Controlled Cyclisation and Interconversion of Oligocholates: Metal Ion Templated "living" Macrolactonisation[END_REF][START_REF] Stadler | Supramolecular Reactions of Metallo-architectures: Ag2-Double-Helicate/Zn4-Grid, Pb4-Grid/Zn4-Grid Interconversions, And Ag2-Double-Helicate Fusion[END_REF] The new compounds are described below.

ii. Characterization of the newly made compounds

A1B1: 1H, H 1 ) 7. 42-7.33 (m, 4H, H 13,13'+14,14' ), 7.33-7.25 (m, 1H, H 15 ), 4.87 (s, 2H, H 11 ); [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] 2,2' ), 129.12 (C 14, 14' ), 128.84 (C 13, 13' ), 127.69 (C 15 ), 127.40 (C 3,3' ), 2,2' ), 129.14 (C 14,14' ), 129.09 (C 13,13' ), 128.70 (C 15 ), 127.38 (C 7.59-7.39 (m, 7H, H 16,6,2+2',15,+15',1,8 ), 3.56 (s, 3H, H 11 ); [START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] 14,14' ), 129.88 (C 1 ), 129.43 (C 15,15' ), 128.16 (C 2,2' ), 127.33 (C 3,3' ), 120.78 (C 6 ), 118.99 (C A8B2: 1 H NMR (500 MHz, CD3CN): δ = 8.28-8.17 (m, 3H, H 2,2'+, 11 The kinetics study of two, three, four-components mixtures

i. Two-component reactions

General procedure for the two-component and three components reactions

All the components were added in the same equivalent and the composition of the DCL was calculated according to the internal standard. In all of the libraries in organic part (in the absence of metal cations), the same equivalent of four components (100 μL, 180 mM for each)

were mixed together in CD3CN, the composition of the DCL was monitored by 1 H NMR as a function of time.

1) The formation of A4B3 from the same equivalent amount of A4 + B3 Table III1. Time-dependent of the evolution of distributions generated from equal amounts of A4 + B3.

Entry t [h] [b]

Compound Distribution

[%] [c] A4 B3 A4B3
1 [a] 0.07 25% 26% 75%

2 [a] 0.2 6% 7% 94%

3 [a] 0.7 1% 2% 99% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

2) The formation of A4B4 from the same equivalent amount of A4 + B4 Table III2. Time-dependent of the evolution of distributions generated from equal amounts of A4 + B4.

Entry t [h] [b]

Compound Distribution [%] [c] A4 A4B4 hemiaminal 1 [a] 0.07 45 <1% 55

2 [a] 52 33 30 37

3 [a] 156 22 62 16 [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

A4 B3 A4B3

A4 B4 A4B4

3) The formation of A5B3 from the same equivalent amount of A5 + B3 Table III3. Time-dependent of the evolution of distributions generated from equal amounts of A5 + B3.

Entry t [h] [b] Compound Distribution [%] [c] A5 B3 A5B3

1 [a] 0.08 92% 93% 8%

2 [a] 1 31% 34% 69%

3 [a] 10 3% 8% 97% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

4)

The formation of A5B4 from the same equivalent amount of A5 + B4 Table III4. Time-dependent of the evolution of distributions generated from equal amounts of A5 + B4.

Entry t [h] [b]

Compound Distribution [%] [c] A5 B4 A5B4

1 [a] 0.08 100% 100% 0%

2 [a] 88 51% 52% 49%

3 [a] 118 43% 44% 57% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

A5 B3 A5B3

A5 B4 A5B4

5) The kinetic data for the formation of A4B3, A4B4, A5B3 and A5B4 from the same equivalent amount of their components Table III5. The formation rates between A4 or A5 and B3 or B4.

Entry [a] reaction product t50[h] [b] t10[h] [c] k (×10 -3 M -1 s - [a] In all of these entries, Aldehyde (30 mM), Amine (30 mM), at room temperature, in CD3CN, monitored by 1 H NMR. [b] Time for 50% completion of the reaction. [c] Time for 10% completion of the reaction. [d] Rate constant calculated from a fit to a second-order reaction over the first 10% of the reaction, reached when the first spectrum recorded. n.d. The reaction is too fast, not calculated.

ii. Three-component reactions 1) Competitive reactions between A4 + B3 + B4

General procedure for the two-component and three components reactions

All the components were added in the same equivalent and the composition of the DCL was calculated according to the internal standard. In all of the reactions in organic part (in the absence of metal cations), the same equivalent of four components (100 μL, 180 mM for each)

were mixed together in CD3CN, the composition of the DCL was monitored by 1 H NMR as a function of time.

Table III6. Time-dependent of the evolution of distributions generated from equal amounts of A4 + B3 + B4.

Entry t [h] [b]

Compound Distribution [%] [c] A4 A4B3 A4B4

1 [a] 0.08 30% 70% <1%

2 [a] 3 6% 53% 41%

3 [a] 24 0% 10% 90% [a] The reaction was performed in CD3CN, 30 mM each, r.t.. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%. 2) Competitive reactions between A5 + B3 + B4 Table III7. Time-dependent of the DCL distributions generated from equal amounts of A5 + B3+ B4.

Entry t [h] [b]

Compound Distribution [%] [c] A5 A5B3 A5B4

1 [a] 0.08 96% 3% 0%

2 [a] 3 27 43% 30%

3 [a] 24 1% 11% 88% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

3) Competitive reactions between A1 + B3 + B4 Table III8. Time-dependent of the evolution of distributions generated from equal amounts of A1 + B3 + B4.

Entry t [h] [b]

Compound Distribution [%] [c] A1 A1B3 A1B4 aminal 1 [a] 0.07 11% 43% <1% 45%

2 [a] 2.5 <1% 45% 51% 6%

3 [a] 23 <1% 8% 92% 0% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

A5

4)

Competitive reactions between A6 + B3 + B4 Table III9.Time-dependent of the evolution of distributions generated from equal amounts of A6 + B3 + B4.

Entry t [h] [b] Compound Distribution [%] [c] A4 A4B1 A4B2

1 [a] 0.4 <1% 87% 13%

2 [a] 5 <1% 46% 54%

3 [a] 29 <1% 12% 88% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

5) Competitive reactions between A3 + B3 + B5

Table III10. Time-dependent of the evolution of distributions generated from equal amounts of A1 + B3 + B5.

Entry t [h] [b]

Compound Distribution [%] [c] A3 A3B2 A3B3 hemiaminal 1 [a] 0.07 51% <1% <1% 48%

2 [a] 162 34% 17% 3% 46%

3 [a] 192 31% 21% 3% 45% [a] The reaction was performed at 25°C. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%. Table III11. Time-dependent of the evolution of distributions generated from equal amounts of B3 and B5 with 2 equiv. A1.

A6

Entry t [h] [b] Compound Distribution [%] [c] A3 A3B2 A3B3 hemiaminal

1 [a] 0.07 54% 1% <1% 44%

2 [a] 93 52% 11% 3% 36%

3 [a] 165 50% 17% 4% 28% [a] The reaction was performed at 25°C. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

iii. Four-component DCLs

General procedure for the experiments of the switching of the DCLs

For all of the quantitative measurements hexamethyldisiloxane (HMDSO) was added as internal standard, T1 relaxation times were determined, and the d1 delay parameter was set to obtain full signal by adjusting d1 to three times the longest T1 relaxation constant in the sample.

All the components were added in the same equivalent and the composition of the DCL was calculated according to the internal standard. In all of the libraries in organic part (in the absence of metal cations), the same equivalent of four components (30 mM for each) were mixed together in CD3CN, the composition of the DCL was monitored by 1 H NMR as a function of time. Table III12. Time-dependent of the evolution of DCL distributions generated from equal amounts of A1 + A6 + B3 + B5.

Entry t [h] [b] Compound Distribution [%] [c] A1 A6 A1B3 A1B5 A6B3 A6B5

1 [a] 0.083 <1% 44% 50% <1% 6% <1%

2 [a] 14 <1% 14% 21% 28% 37% 5%

3 [a] 96 <1% <1% 9% 41% 38% 12% [a] The reaction was performed at 25°C. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

2) DCL generated from equal amounts of A4 + A5 + B3 + B4 Table III13. Time-dependent of the evolution of DCL distributions generated from equal amounts of A4 + A5 + B3 + B4.

Entry t [h] [b]

Compound Distribution [%] [c] A4 A5 A4B3 A4B4 A5B3 A5B4

1 [a] 0.4 1% 44% 36% 13% 6% 1%

2 [a] 5 <1% 11% 15% 35% 29% 12%

3 [a] 15 <1% 2% 14% 36% 35% 14% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

3) DCL generated from equal amounts of A4 + A6 + B3 + B4. Table III14. Time-dependent of the evolution of DCL distributions generated from equal amounts of A4 + A6 + B3 + B4.

Entry t [h] [b]

Compound Distribution [%] [c] A4 A6 A4B3 A4B4 A6B3 A6B4

1 [a] 0.083 4% 42% 34% 3% 6% 2%

2 [a] 3.5 2% 6% 13% 34% 35% 11%

3 [a] 12 0% 4% 12% 39% 37% 8% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%. Table III15. Time-dependent of the evolution of DCL distributions generated from equal amounts of A4 + A7 + B3 + B4

Entry t [h] [b] Compound Distribution [%] [c] A4 A7 A4B3 A4B4 A7B3 A7B4

1 [a] 0.08 1% 40% 36% 8% 14% 2%

2 [a] 0.75 0% 10% 14% 31% 36% 13%

3 [a] 2.3 0% 2% 13% 39% 36% 15% [a] The reaction was performed in CD3CN, 30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%. [b] Compound Distribution [%] [c] A1 A6 A1B3 A1B4 A6B3 A6B4

1 [a] 0.083 3% 44% 32% 14% 6% 1%

2 [a] 0.5 0% 19% 14% 37% 29% 4%

3 [a] 4 0% 1% 9% 41% 43% 7% [a] The reaction was performed at 25°C. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

6)

DCL generated from equal amounts of A1 + A4 + B3 + B5 Table III17. Time-dependent of the evolution of DCL distributions generated from equal amounts of A1 + A4 + B3 + B5.

Entry t [h] [b]

Compound Distribution [%] [c] A1 A4 A1B3 A1B5 A4B3 A4B5

iv. Four-component DCLs in the presence of metal ions

For the experiments in inorganic part (in the presence of AgOTf and Zn(OTf)2), the same equivalent of four components (10 mM) (because of the solubility) together with 0.5 equiv.

AgOTf (5 mM) and 0.5 equiv. Zn(OTf)2 (5 mM) were mixed at the same time in CD3CN, the composition of the DCL was monitored by 1 H NMR as a function of time. The composition of the DCLs was determined by comparison with the internal standard.

1) DCL generated from equal amounts of A1 + A8 + B1 + B2 in presence of 0.5 equiv. of AgOTf and Zn(OTf)2

Table III18. Time-dependent of the evolution of DCL distributions generated from equal amounts of A1 + A8 + B1 + B2 (10 mM each) in the presence of both AgOTf (0.5 equiv., 5 mM) and Zn(OTf)2 (0.5 equiv., 5 mM).

Entry t [h] [b] Compound Distribution [%] [c] A8 A1 [Ag(A1B1)2] + [Zn(A1B2)2] 2+ A8B4 A8B5

1 [a] 1 50% <1% 48% <1% <1% 0%

2 [a] 70 5% <1% 10% 41% 38% 6% [a] The reaction was performed in CD3CN, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

Quantitative integration of DCL[5] (A1 + A8 + B1 + B2) in presence of AgOTf and Zn(OTf)2

after 1 h and 70 h. 2) DCL generated from equal amounts of A2 + A8 + B1 + B2 in presence of 0.5 equiv. of AgOTf and Zn(OTf)2

Table III19. Time-dependent of the evolution of DCL [5] distributions generated from equal amounts of A2 + A8 + B1 + B2 (10 mM each) in the presence of both AgOTf (0.5 equiv., 5 mM) and Zn(OTf)2 (0.5 equiv., 5 mM).

Entry t [h] [c] Compound Distribution [%] [d] A8 A2 [Ag(A2B1)2] + [Zn(A2B2)2] 2+ A8B1 A8B2

1 [a] 1 49% 3% 47% <1% 1% <1%

2 [b] 2 days 10% <1% 11% 39% 40% <1% [a] The reaction was performed in CD3CN, r.t. [b] The reaction was performed at 60°C. [c] Reaction times indicate the time at which distribution data were collected. [d] Error in 1 H-NMR signal integration: 5%.

Quantitative integration of DCL[6] (A2+A8+B1+B2) in presence of AgOTf and Zn(OTf)2 after 1 h and heating for 2 days

. 1 H NMR (600 MHz) spectra of the mixture generated from equal amounts of A2 + A8 + B1 + B2 (10 mM each, CD3CN) + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 after 1 h (bottom) and after heating for 2 days (top).

3) DCL generated from equal amounts of A3 + A8 + B1 + B2 in presence of 0.5 equiv. of AgOTf and Zn(OTf)2

Table III20. Time-dependent of the evolution of DCL [6] distributions generated from equal amounts of A8+A6+B4+B5 (10 mM) in the presence of both AgOTf (0.5 equiv., 5 mM) and Zn(OTf)2 (0.5 equiv., 5 mM).

Entry t [h] [c] Compound Distribution [%] [d] A8 A3 [Ag(A3B1)2] + [Zn(A3B2)2] 2+ A8B1 A8B2

1 [a] 1 46% 1% 48% <1% 1% 8%

2 [b] 2 days 6% <1% 11% 43% 2% <1% [a] The reaction was performed at 25°C. [b] The reaction was performed at 60°C. [c] Reaction times indicate the time at which distribution data were collected. [d] Error in 1 H-NMR signal integration: 5%. 5) 1 H NMR spectra of all the components and constituents in the absence of presence of metal salts 2) Procedures for quantitative calculation of the imine yield

Quantitative integration of DCL[7] (A3+A8+B1+B2) in presence of AgOTf and Zn(OTf)2 after 1 h and 2 days (heating).

In a typical experiment, the stock solution of aldehydes (30 mM), the amine or hydrazine By (30 mM), and the internal standard (sodium trimethylsilylpropylsulfonate) (20 mM) was prepared in advance. And then the same volume (100 μL) of Ax and By were mixed together with the internal standard (10 μL) in phosphate buffer (600 μL). After vigorous shaking and 10 minutes, the resulting mixture was monitored at 25°C by 1 H NMR.

3) Procedures for titration experiment

The equimolar amount of the aldehyde and N-α-Lysine (5mM) was mixed together in

Résumé en anglais

In this thesis, we have explored the formation of C=N compounds: the kinetics and catalysis of C=N formation, the time-dependent switching of dynamic covalent libraries as well as the enhanced imine formation in aqueous phase. First, imine and hydrazone formation were greatly accelerated in the presence of metal salts as catalysts. The simultaneous operation of amine and metal salts displayed a synergistic catalysis on hydrazone formation. Second, the [2 × 2] DCL achieve a time-dependent switching from a kinetic distribution to thermodynamic distribution by screening of the components both in the absence and presence of two metal salts Ag(I) and Zn(II). Thirdly, from the thermodynamic point of view, the imine formation in aqueous phase was greatly enhanced through adjusting different factors to accelerate and stabilize the generated imine products. KEYWORDS: Constitutional dynamic chemistry, Dynamic covalent chemistry, Dynamic covalent libraries, Out-of-equilibrium states, Kinetic switching of DCLs

Schéma 1 .

 1 photosensible des cellules de la rétine) et dans le métabolisme des acides aminés. Il s'agit de l'une des liaisons dynamiques les plus utilisées dans le domaine de la DCvC. De nombreux groupes l'ont étudié de manière approfondie, y compris le nôtre. Bien que les études cinétiques et thermodynamiques sur les bases de Schiff individuelles soient assez abondantes, seules quelques-unes se focalisent sur le comportement des azométhines dans les CDLs. Dans cette thèse, notre but est d'élargir nos connaissances sur la liaison imine et à les utiliser pour étudier différents comportements adaptatifs d'un point de vue cinétique et thermodynamique, y compris les commutateurs de CDNs et leurs états hors-équilibre (Chapitre II et III). De plus, d'un point de vue thermodynamique, tout en développant des imines pour

  De plus, la formation d'hydrazone a été accélérée par un facteur similaire à l'aide d'une organocatalyse avec l'amine auxiliaire : la p-anisidine. Grâce à une contribution mutuelle entre Zn(OTf)2 et la p-anisidine, la vitesse de formation du complexe de zinc de l'hydrazone a été augmentée d'un facteur d'environ 630 par rapport à la formation de l'hydrazone sans aucun catalyseur. Une réaction rapide a également été observée dans une configuration à trois catalyseurs, combinant les deux sels métalliques et l'amine auxiliaire. Ainsi, les deux sels métalliques et l'amine induisent une accélération synergique importante de la formation du complexe d'hydrazone du Zn(II). xvi Combinant à la fois métallo et organocatalyse, cet effet synergique indique que l'utilisation de co-catalyseurs est une stratégie intéressante pour accélérer la formation de liaisons C=N. Il démontre que les systèmes dynamiques peuvent générer des résultats cinétiquement plus rapides et thermodynamiquement plus simples à partir de systèmes dynamiques complexes utilisant la CDC. Les réactions covalentes dynamiques sont utilisées pour la construction de DCLs capables de s'adapter aux effecteurs externes, ce qui se traduit par des changements dans la constitution de la bibliothèque suite à la sélection des composants. Nous avons exploré le comportement des DCLs composées de quatre constituants générés par la formation réversible de liaisons C=N entre quatre composants (deux aldéhydes A, A' et deux amines B, B'), sans et avec cations métalliques (Figure 1).

Figure 1 .

 1 Figure 1. Évolution d'une CDL de quatre constituants subissant une commutation orthogonale en fonction du temps.

Figure 2 .

 2 Figure 2. Les aldéhydes sélectionnés pour former l'imine en phase aqueuse (haut), ainsi que les rendements de formation d'imine en fonction du pH (bas).

Figure 3 .

 3 Figure 3. The three early supramolecular host molecules

Figure 4 .

 4 Figure 4. The self-assembly of circular helicates from the ligands and the Fe(II) ions in the presence of different anions (chloride or sulfate anions).[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF]

Figure 5 .

 5 Figure 5. Self-recognition in the self-assembly of the double helicate and the triple helicate from a mixture of the oligobipyridine strands and of CuClO4 and Ni(ClO4)2.

Figure 7 .

 7 Figure7. Molecular components spontaneously self-organize into a constitutional dynamic library (CDL) of interconverting supramolecular or molecular constituents. The addition of chemical effectors (perturbation) induces the selective formation of the two constituents providing the best interactions with the effectors.[START_REF] Ayme | Chapter One -From Coordination Chemistry to Adaptive Chemistry[END_REF]

Figure 9 .

 9 Figure 9.The amplification of the best enzyme inhibitor from the virtual combinatorial library of imine constituents.

Scheme 1 .

 1 Scheme 1). The constituent A shares component with B and C, so if the concentration of A increases, that of B and C must decrease, they (A and B or C) have antagonistic connectivity where are connected by edges; however, A does not share any component with D, if the concentration of A increases, the concentration of D has to increase, thus they (A and D or B and C) have the agonistic connectivity, shown by the diagonals. Due to its dynamic features,

Figure 10 .

 10 Figure10. The adaptative behavior of a [2 × 2] DCL generated from four components on addition of two different effectors.[START_REF] Holub | Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information[END_REF][START_REF] Ayme | Chapter One -From Coordination Chemistry to Adaptive Chemistry[END_REF]

Figure 11 .

 11 Figure11. The switching of dynamic covalent reaction network consisting of a sensitized and a nonsensitized photocleavable alkoxyamines between equilibrium and out-of-equilibrium states through Light and heat.[START_REF] Herder | The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool To Shift Reaction Networks Out-of-Equilibrium Using Light Energy[END_REF]

  established two DCLs of imine constituents in a mixed solvent of acetonitrile/water shown in Figure 12. Through screening of the components, one of the two libraries are generated from 1, 2, 3 and 4 to form four imines possessing hydrophilic-hydrophilic (5), hydrophobic-hydrophobic (8), or amphiphilic characteristics (6 and 7). The DCL could undergo recombination through component exchange reactions upon phase separation induced by cooling and heating. The phase separation led to amplification of 5 and 8 and down-regulation of 6 and 7. This adaptive process indicated that the constitution of a DCL can also be changed by a phase change, laying a foundation to development of new effectors for constitution change of a DCL.

Figure 12 .

 12 Figure 12. Dynamic covalent library of imines 5-8 generated by reaction of the biogenic amines 1 and 2 with the aldehydes 3 and 4.

Figure 13 . 4 PHOTOSELECTION

 134 Figure 13. Adaptation of the [2 × 2] DCL of four constituents E-1 A 1 C, 1 A 3 C, 2 A 1 C, and 2 A 3 C by variation of the distributions under (left) metalloselection on addition of zinc(II) and (right) photoselection by photoisomerization of E-1 A 1 C into Z-1 A 1 C on light irradiation.

5

  and Fe(II) favors 6 in this system. The study of the subsystems of the four components 1, 2, 5 and 6 in the presence of two metal ions Fe(II) and Zn(II) indicated the formation of the kineticproduct [Zn(1, 2)2] 2+, which appeared at the beginning and then slowly decreased to form the thermodynamic product [Zn(5, 6)2] 2+ and [Fe(1, 2)2]2+ . This work demonstrated that a simpler output could be generated through the self-sorting of systems with high complexity by screening of the components and metal ions. And it is important to note that kinetic trapped molecules may be generated in the multiple complex system.

Figure 14 .

 14 Figure 14. The concomitant formation of complexes [Fe(1,2)2] 2+ , [Cu(3,4)2] + , and [Zn(5,6)2] 2+ through the hetero-self-sorting of their initial reactants.[START_REF] Ayme | Triple Self-Sorting in Constitutional Dynamic Networks: Parallel Generation of Imine-Based CuI, FeII, and ZnII Complexes[END_REF]

Figure 16 .Scheme 5 .

 165 Figure 16. Hydrazone reaction of AcGRGDSGG-Hydrazide 1 and Glyoxylyl-LYRAG 2 in the absence or presence of aniline to form the acylhydrazone 3.

Scheme 6 .

 6 Scheme 6. The general mechanism of transimination.187

Scheme 9 .

 9 Scheme 9. Transimination reactions between A and C; B and D.

Figure 18. 1 H

 1 Figure 18.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B1 (10 mM each, CD3CN, 25°C) in the presence of Ag(OTf) after 20 min, 2 h, 5 h and 44 h (from bottom to top). A reference spectrum of the separately prepared constituent [Ag(A1B1) 2 ] + is shown above.

Figure 21. 1 H

 1 Figure 21.1 H NMR (500 MHz) spectra for the titration of a mixture of A1 and B1 with different equivalents of Zn(OTf)2 in CD3CN at 25°C (The initial concentration of A1 or B1 was 10 mM each).

Figure

  Figure 22.Low temperature (-35°C ) 1 H NMR spectra obtained from three experiments: from bottom to top: A1B1: Zn(OTf)2 = 2 : 1; A1B1: Zn(OTf)2 = 3 : 1; A1B1. The concentration of A1B1 is 10 mM.

Figure

  Figure 23.The single crystal structure of [Zn(A1B1)2(CF3SO3)2] obtained from 1.0 equiv. A1B1 and 0.5 equiv. Zn(II) from the system of CH3CN/diethyl ether.

Figure 24 .

 24 Figure24.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B1 (10 mM each) in CD3CN at 25°C after 1 h, 24 h, 60 h, 246 h (from bottom to top). A reference spectrum of the separately prepared constituent A2B1 is shown above.

Figure 25 . 1 H

 251 Figure25.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B1 (10 mM each) in CD3CN at 25°C after 5 minutes, 4 h, 12 h, 36 h (from bottom to top). A reference spectrum of the separately prepared constituent A3B1 is shown above.

Figure 26 .

 26 Figure 26. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B1 (10 mM each) + 0.5 equiv. AgOTf (5 mM) in CD3CN at 25°C after 20 min, 2 h, 5 h and 44 h (from bottom to top). A reference spectrum of the separately prepared constituent [Ag(A2B1)2] + is shown above.

Figure

  Figure 27.The single crystal structure of [Ag(A2B1)2] obtained from 1.0 equiv. A2B1 and 0.5 equiv. Ag(I) dissolved in CH3CN/diethyl ether.

Figure 28 .

 28 Figure 28. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B1 (10 mM each) + 0.5 equiv. AgOTf (5 mM) in CD3CN at 25°C after 20 min, 2 h, 5 h, 44 h (from bottom to top). A reference spectrum of the separately prepared constituent [Ag(A3B1)2] + is shown above.

Figure

  Figure 29.The single crystal structure of [Ag(A3B1)2] obtained from 1.0 equiv. A3B1 and 0.5 equiv. Ag(I) dissolved in CH3CN/diethyl ether.

Figure 30 . 1 H

 301 Figure30.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B1 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 minutes.

Figure 31 . 1 H

 311 Figure31.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B1 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 minutes.

Scheme 18 .

 18 Scheme 18. Hydrazone formation from a pyridine-2-carboxaldehyde derivative A1 (A2 or A3) and 2-Nmethylhydrazino-pyridine B2 in the absence and presence of metal salts [AgOTf or Zn(OTf)2]. k1', k1s', k1z', k2', k2s', k2z', k3', k3s', k3z' are the initial formation rate constants, their values being estimated from the formation of 10% product using a second order kinetic equation.

Figure 32 .

 32 Figure32.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 (10 mM each, CD3CN, 25°C) after 5 minutes, 31 h, 97 h, 154 h (from bottom to top). A reference spectrum of the separately prepared constituent A1B2 is shown above.

Figure 33 .

 33 Figure 33. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 (10 mM each, CD3CN, 25°C) + 0.5 equiv. of AgOTf (5 mM) after 5 minutes, 20 min, 4 h, 17 h (from bottom to top).

  only 8-fold. As for Ag(I), NMR spectroscopy showed a clear interaction between Zn(II) and B2, an interaction which presumably diminished acceleration of the overall reaction by Zn(II) in the same ways as for Ag(I). An X-ray structure determination on the isolated complex [Zn(A1B2)2](CF3SO3)2.CH3CN (Figure35) showed the Zn(II) to be in octahedral N6 coordination with each ligand bound in a tridentate mode. The asymmetric unit contains one molecule of the complex, two triflate and one molecule of the acetonitrile solvent. The atoms of one molecule of triflate are disordered over two positions.

Figure 34. 1 H

 1 Figure 34. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 (10 mM each, CD3CN, 25°C) + 0.5 equiv. of Zn(OTf)2 (5 mM) after 5 minutes, 5 h, 19 h, 63 h (from bottom to top). A reference spectrum of the separately prepared constituent [Zn(A1B2)2](CF3SO3)2 is shown above.

Figure

  Figure 35.The single crystal structure of [Zn(A1B2)2] obtained from 1.0 equiv. of A1B2 and 0.5 equiv. of Zn(II) triflate dissolved in CH3CN/diethyl ether.

Figure 42 )

 42 Figure 42). The kinetic curves and rate constants are shown in Figure 43 and Figure 44. The accelerations induced by addition of the given amount of Ag(I) amount to factors of 19 and 2

Figure 36 .

 36 Figure36.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 (10 mM each) in CD3CN at 25°C after 5 minutes, 30 min, 60 h, 253 h (from bottom to top). A reference spectrum of the separately prepared constituent A2B2 is shown above.

Figure 37 . 1 H

 371 Figure37.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B2 (10 mM each) in CD3CN at 25°C after 5 min, 4 h, 26 h and 97 h (from bottom to top). A reference spectrum of the separately prepared constituent A3B2 is shown above.

Figure 38 .

 38 Figure38.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 (10 mM each) + 0.5 equiv. of AgOTf (5 mM) in CD3CN at 25°C after 5 min, 30 min, 4 h, 18 h (from bottom to top).

Figure 39 . 1 H

 391 Figure39.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B2 (10 mM each) + 0.5 equiv. of AgOTf (5 mM) in CD3CN at 25°C after 5 min,3.5 h, 7.5 h, 18 h.

Figure 40 .

 40 Figure 40. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 minutes, 4 h, 17 h, 63 h (from bottom to top). A reference spectrum of the separately prepared constituent [Zn(A2B2)2] 2+ is shown above.

Figure

  Figure 41.The single crystal structure of [Zn(A2B2)2](CF3SO3)2.CH3CN obtained from 1.0 equiv. A2B2 and 0.5 equiv. Zn(II) from the system of CH3CN/diethyl ether.

Figure 42 . 1 H

 421 Figure42.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B2 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 minutes, 17 h, 47 h, 63 h (from bottom to top). A reference spectrum of the separately prepared constituent [Zn(A3B2)2] 2+ is shown above.

Figure 43 .

 43 Figure 43. Plots of the evolution of a mixture of equal amounts of components (A). A1/A2/A3 + B2; (B).A1/A2/A3 + B2 + 0.5 equiv. AgOTf;(C). A1/A2/A3 + B2 + 0.5 equiv. Zn(OTf)2; (D). A1 + B2, A1 + B2 + 0.5 equiv. AgOTf and A1 + B2 + 0.5 equiv. Zn(OTf)2; (E). A2 + B2, A2 + B2 + 0.5 equiv. AgOTf and A2 + B2 + 0.5 equiv. Zn(OTf)2; (F). A3 + B2, A3 + B2 + 0.5 equiv. AgOTf and A3 + B2 + 0.5 equiv. Zn(OTf)2 as a function of time as obtained from integration of the imine CH=N proton signal in the 500 MHz 1 H NMR spectra (10 mM each, CD3CN, 25°C).

Figure 45 . 1 HFigure 46 . 1 H

 451461 Figure45.1 H NMR spectra of the separately prepared zinc complex from 0.5 equiv. of Zn(II) and 1.0 equiv. of B2 (10 mM) in CD3CN at 25°C .

Figure 47 .

 47 Figure 47. HRMS-ESI spectrum of [Zn(B2)2] 2+ obtained in situ from 2 equiv. B2 (20 mM) and 1 equiv. Zn(OTf)2 (10 mM) in CH3CN. Measured (top), simulated (bottom).

52 . 19 .

 5219 Scheme 19. Hydrazone formation from pyridine-2-carboxaldehyde A1 (A2 or A3) and B2 in the presence of (i) B1 alone or together with either AgOTf or Zn(OTf)2 as well as hydrazone formation from A1B1 and B2 and [Zn(A1B2)2] 2+ formation from [Zn(A1B1)2] 2+ and B2.k1a, k1as, k1az, k1i, k1iz, k2a, k2as, k2az, k3a, k3as, k3az are the initial corresponding formation rate constants calculated from the formation of 10% product using a second order kinetic equation. For the structures of A1B1, and [Zn(A1B1)2] 2+ see Scheme 15.

Figure 48 .

 48 Figure48.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 + B1 (10 mM each, CD3CN, 25°C) after 10 min, 5 h, 15 h, 54 h from bottom to top. Reference spectra (top two traces) are of the separately prepared constituents A1B1, A1B2.

Figure 52 .

 52 Figure 52.

Figure 49 .

 49 Figure49.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 + B1 + 0.5 equiv. AgOTf (10 mM each, CD3CN, 25°C) after 5 min, 1 h, 4 h, 9 h from bottom to top. A reference spectrum of the separately prepared constituent [Ag(A1B2)2] + is shown above.

  with 26% of [Zn(A1B2)2] 2+ . Minor signals indicated the presence of other combinations of A1, B1, B2 and Zn(II) but the signal broadening seen in several instances during this thesis work with mixtures containing Zn(II) rendered identification of intermediate species difficult.

Figure 50 .

 50 Figure 50. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 + B1 (10 mM each, CD3CN, 25°C) + Zn(OTf)2 (5 mM each) after 5 min, 15 min, 2 h, 4 h from bottom to top. Reference spectrum of the separately prepared constituent [Zn(A1B2)2] 2+ .

Figure 51 .

 51 Figure 51. Low temperature 1 H NMR spectra obtained from mixing the same amount of A1 + B2 in presence of 1.0 equiv. B1 and 0.5 equiv. Zn(II) starting from -35°C to +25°C in steps of 10 degrees (10 mM each, CD3CN).

Figure 52 .

 52 Figure 52.Comparative (A) kinetic curves obtained as a function of time from integration of the imine CH=N proton signal in the 500 MHz 1 H NMR spectra (10 mM each, CD3CN, 25°C) and (B) initial rate constants (k) calculated from a fit to a second-order reaction over the first 10% of the reaction for the hydrazone formation process between A1 and B2 (Scheme 19) in the absence of catalyst and in the presence of B1 or a metal salt, AgOTf or Zn(OTf)2 separately, as well as B1 and AgOTf or B1 and Zn(OTf)2 together as co-catalysts along with the additional control reactions of A1B1 with B2 and [Zn(A1B1)2] 2+ with B2. Note that the curves for A1 + B2 + B1 + Zn(II) and for [Zn(A1B1)2] 2+ + B2 are superimposed.

the 1 H

 1 NMR spectrum became broad due to relatively slow exchange reactions of intermediate Zn(II) complexes. Nonetheless signal integrations indicated a composition of about 37% of B2 coordinated to zinc, 35% complexed imine A1B1 (imine CH signal at 8.7 ppm), 38%[Zn(A1B2)n] 2+ (imine CH=N signal at 7.6 ppm), 65% of free B1 and the remainder [about 25% A1, 25% B2 and possibly mixed-ligand complexes of Zn(II)] accounted for other signals in the spectrum. The mixture evolved until after 2 h the zinc complex [Zn(A1B2)2] 2+ was fully (97%) formed with liberation of 1 equiv. of free B1 (0.64 M -1 s -1 ).

Figure 53 . 1 H

 531 Figure53.1 H NMR (500 MHz) spectra from bottom to top: a) A1B1; b) A1B1 (10 mM) + 0.5 equiv. Zn(OTf)2; c) A1B1 (10 mM each) + 0.5 equiv. Zn(OTf)2 + B2 (10 mM) after 5 min; d) A1B1 (10 mM each) + 0.5 equiv. Zn(OTf)2 + B2 (10 mM) after 20 min; e) A1B1 (10 mM each) + 0.5 equiv. Zn(OTf)2 + B1 (10 mM) after 2 h; e) reference spectrum of the separately constituent [Zn(A1B2]2] 2+ .

Figure 54 .

 54 Figure54.1 H NMR (500 MHz) spectra from bottom to top: a) A1 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2; b) A1 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2 + B1 (10 mM) after 4 min; c) A1 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2 + B1 (10 mM) after 9 min; d) A1 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2 + B1 (10 mM) after 30 min; e) reference spectra B2 (10 mM) + 0.5 equiv. Zn(OTf)2; f) reference spectrum of the separately prepared constituent A1B1; g) reference spectrum of the separately prepared constituent [Zn(A1B2]2] 2+ .

Figure 55 .

 55 Figure55.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1B1 + B2 (10 mM each, CD3CN, 25°C) after 5 min, 2 h, 5 h, 10 h from bottom to top. Two reference spectra of the separately prepared constituents A1B1, A1B2 were shown above.

Scheme 20 .

 20 Scheme 20. Proposed schematic mechanism for the formation of the zinc complex [Zn(A1B2)2] 2+ from A1 + B2 in presence of both Zn(OTf)2 and B1 acting in a synergistic co-catalysis pathway. The formation of [Zn(A1B2)2] 2+ could also proceed in two successive steps.

Figure 56 .

 56 Figure56.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 + B1 (10 mM each) in CD3CN at 25°C after 10 min, 15 h, 25 h, 47 h from bottom to top. Two reference spectra (top two traces) of the separately prepared constituents A2B1, A2B2 were shown above.

Figure 57 .

 57 Figure57.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 + B1 (10 mM each) + 0.5 equiv. AgOTf (5 mM) in CD3CN at 25°C after 5 min, 1 h, 4 h, 9 h from bottom to top. A reference spectrum of the separately prepared constituent [Ag(A2B2)2] + is shown above.

Figure 58 .

 58 Figure 58. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 + B1 (10 mM each) + Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 min, 20 min, 40 min, 3 h from bottom to top. A reference spectrum of the separately prepared constituent [Zn(A2B2)2] 2+ is shown above.

Figure 59 .

 59 Figure 59. Comparative (A). kinetic curves and (B). initial rate constants for the hydrazone formation process between A2 and B2 (Scheme 19) in the absence of catalyst and presence of B1 or a metal salt, AgOTf or Zn(OTf)2 separately, as well as B1 and AgOTf or B1 and Zn(OTf)2 together as co-catalysts in CD3CN at 25°C; The numbers above the columns correspond to 10 3 k for ease of comparison (error on calculated rate constant of about 5%).

Figure 60 .

 60 Figure60.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B2 + B1 (10 mM each) in CD3CN at 25°C after 5 min, 2 h, 5 h, 11 h from bottom to top. Two reference spectra (top two traces) of the separately prepared constituents A3B1, A3B2 are shown above.

Figure 61 .

 61 Figure61.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B2 + B1 (10 mM each) + AgOTf (5 mM) in CD3CN at 25°C after 5 min, 1 h, 3 h, 7 h from bottom to top. A reference spectrum of the separately prepared constituent [Ag(A3B2)2] + is shown above.

Figure 62 .

 62 Figure 62. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A3 + B2 + B1 (10 mM each) + Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 min, 10 min, 1 h, 2 h from bottom to top. Reference spectra (top two traces) of the separately prepared constituents A3B1, [Zn(A3B2)2] 2+ are shown bove.

Figure 63 .

 63 Figure 63. Comparative (A). kinetic curves and (B). initial rate constant (k) for the hydrazone formation process between A3 and B2 (Scheme 19) in absence of catalyst and in presence of B1 or a metal salt, AgOTf or Zn(OTf)2 separately, as well as B1 and AgOTf or B1 and Zn(OTf)2 together as co-catalysts along in CD3CN at 25°C. The numbers above the columns correspond to 10 3 k for ease of comparison.

Figure 64 .

 64 Figure 64. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 + B1 (10 mM each, CD3CN, 25°C) + AgOTf + Zn(OTf)2 (5 mM each) after 10 min, 4 h, 13 h, 25 h from bottom to top. Two reference spectra (top two traces) of the separately prepared constituents [Ag(A1B1)2] + , [Zn(A1B2)2] 2+ are shown above.

Figure 65 . 2 Figure 66 .

 65266 Figure 65. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 + B1 (10 mM each) + AgOTf (5 mM) + Zn(OTf)2 (5 mM) in CD3CN at 25°C after 5 min, 4 h, 15 h, 78 h from bottom to top. Two reference spectra (top two traces) of the separately prepared constituents [Ag(A2B1)2] + , [Zn(A2B2)2] 2+ are shown above.

Figure 67 .CompositionFigure 68 .

 6768 Figure 67. Kinetic plots of the evolution of: (A) imine A1B1 formation from a mixture of equal amounts of components A1 + B1 in absence of catalyst or in presence of catalysts as indicated; (B) zoom of a); (C) hydrazone A1B2 formation from a mixture of equal amounts of components A1 + B2 in absence of catalyst or in presence of catalysts as indicated; (D) zoom of c). Data obtained as a function of time from integration of the CH=N proton signal in the 500 MHz 1 H NMR spectra (10 mM each, CD3CN, 25°C).

Figure 69 .

 69 Figure 69. 1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 + 0.05 equiv. Zn(OTf)2 (10 mM each, CD3CN, 25°C) after 5 min,10.5 h, 45 h from bottom to top. Reference spectra (top two traces) of the separately prepared constituents A1B2, [Zn(A1B2)2] 2+ .

Figure 70 .

 70 Figure 70. The adaptation of the DCL either to the equilibrium or to photogeneration of the out-ofequilibrium state of the receptor through binding to the best constituent.58

[ 5 × 5 ]

 55 DCL containing presumably 25 imines from 5 aldehydes(1, 2, 3, 4, 5) and 5 amines (A, B, C, D, E), the first fraction of the distillated product was the 1A with 77% yield as the lightest imine at the expense of other imines sharing the same component with 1A including imines 1B-1E, 2A, 3A, 4A and 5A. The second observed fraction was 2B with a yield of 80% between the temperature of 90-120℃. Similarly, the imines shared the components with 2B was all eliminated during the distillation process including 2C-E, 3B, 4B, and 5B. Further distillation of the left DCL generated 3C (80%, 130-140°C ) and 4D (73%, 240°C ) consecutively and 5E was left in the distillation flask in 80% yield. Through distillation of the[5 × 5] DCL, five imines were generated and separated from the possible 25 imines. In the distillation process, both the rates of the distillation and the thermodynamic equilibration play important roles to achieve this self-sorting behavior. This kinetic control of the self-sorting of the DCLs provided new ways to achieve the selection and amplification of the constituents within the DCLs.

Figure 71.Self -

 71.Self Figure 71.Self-sorting of a dynamic [5 × 5] imine library during a slow vacuum distillation.

[ 2 × 2 ]

 22 DCL was generated from 4 components 3 A,4 A,1 C and 1 D with the formation of four constituents 3 A 1 C, 3 A 1 D, 4 A 1 C, 4 A 1 D with a statistical distribution where the four constituents have similar composition. The addition of one effector CuOTf resulted in the formation of the Cu(I) complex of 3 A 1 D and the amplification of its agonist 4 A 1 C. On the other hand, the addition of Zn(OTf)2 led to the formation of the Zn(II) complex of 3 A 1 C with the amplification of its agonist 4 A 1 D. Both two adaptations are the result of the thermodynamic control. However, by removal of either Zn(II) or Cu(I) from the two equilibrium states, the two corresponding outof-equilibrium states were generated with only two constituents 3 A 1 C, and 4 A 1 D (or 3 A 1 D and 4 A 1 C) in the DCL, which cannot be obtained under thermodynamic conditions. With the readdition of the two metal ions, the DCL can be rapidly transformed back to the two equilibrium states. This work displayed the full circle of the switching between the equilibrium states and out-of-equilibrium states through addition and removal of metal ions to the DCLs of imines. It indicated that the kinetic behavior of the DCLs can be selectively controlled to find applications of training a CDN for the storage, recall and erasing of information for effector recognition.

Figure 72 .

 72 Figure 72. Representation of All of the Transformations Performed by the Dual Responsive Dynamic Covalent System Based on the DCL 3 A 1 C, 3 A 1 D, 4 A 1 C, 4 A 1 D.

  Scheme 21. Evolution of a DCL of four constituents undergoing a time-dependent orthogonal switching of its associated[2 × 2] CDN from one diagonal to the other one.

Scheme 21 ,Scheme 22 .

 2122 Scheme 22. The structure of the selected aldehydes and amines to set up the [2 x 2] DCLs. The compositions of the DCLs given below have been determined by integration of characteristic 1 H NMR signals (-CHO, -CH=N, aromatic -H, -CH2, -CH3) with respect to the proton signal (at 0.06 ppm) of hexamethyldisiloxane (HMDSO) as internal standard. The sum of the % for each component in the different entities present in the DCL is equal to 50%, the maximum any constituent can reach. The error in 1 H NMR integration amounts to about 5%.

Figure 73 .

 73 Figure73.1 H NMR (400 MHz) spectra of the mixture of equimolar amount A4 and B3 (30 mM each, CD3CN, 25°C) after 4 min, 12 min, 44 min (three bottom traces). A reference spectrum of the separately prepared constituent A4B3 is shown above.

Figure 74 .

 74 Figure74.1 H NMR (400 MHz) spectra of the mixture of equimolar amount of A4 and B4 (30 mM each, CD3CN, 25°C) after 5 min, 52 h, 156 h (three bottom traces). A reference spectrum of the separately prepared constituent A4B4 is shown above.

Figure 75 . 1 HFigure 76 .

 75176 Figure75.1 H NMR (400 MHz) spectra of the mixture of equimolar amount of A5 and B3 (30 mM each, CD3CN, 25°C) after 5 min, 1 h, 10 h (three bottom traces). A reference spectrum of the separately prepared constituent A5B3 is shown above.

Figure 77 .

 77 Figure 77. Kinetic plots of the evolution of a mixture of equimolar components (A). A4 + B3; (B). A4 + B4; (C). A5 + B3; (D). A5 + B4 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ).

2 )

 2 Figure 81A.

Figure 78 . 1 H

 781 Figure78.1 H NMR (400 MHz) spectra of the equimolar mixture of A4, B3 and B4 (30 mM each, CD3CN, 25°C ) after 5 minutes, 5 h and 24 h (three bottom traces). The two top traces correspond to the isolated constituents A4B3 and A4B4.

Figure 79 . 1 H

 791 Figure 79. 1 H NMR (400 MHz) spectra of the mixture of the same equivalent of A5, B3 and B4 (30 mM each, CD3CN, 25°C) after 5 minutes, 25 min and 24 h (three bottom traces). Two reference spectra of the isolated constituents A5B3 and A5B4 are shown above.As a complementary experiment, the reaction of [A4 + A5 + B3] with equimolar amount of components was also conducted (Figure80). In the beginning after 5 minutes, only A4B3 is observed. Then it is very slow for the exchange of A4B3 with A5. After 24 hours, there is less than 10% A5B3 formation. It proves again A4 is a much more reactive aldehyde than A5. The kinetics curve of this set of reaction is shown in Figure81C. The set of [A4 + A5 + B4] was also tried but it was too slow to follow the kinetics even for the exchange reaction between A4B4 with A5.

Figure 80 .

 80 Figure80.1 H NMR (400 MHz) spectra of the mixture of equimolar amount of A4, A5 and B3 (30 mM each, CD3CN, 25°C ) after 5 minutes, 5 h and 24 h (three bottom traces). The two top traces correspond to the isolated constituents A4B3 and A5B3.

Figure 81 .

 81 Figure 81. Kinetic plots of the evolution of a mixture of equimolar amount of components (A). A4 + B3 + B4; (B). A5 + B3 + B4; (C). A4 + A5 + B3 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ). The kinetic curves are shown for only some of the compounds for clarity.

Figure 83 .

 83 Figure 83. The whole process displayed a kinetic switching behavior of the CDN associated to DCL[1] from the diagonal [A4B3, A5 + B4] to the orthogonal diagonal [A4B4, A5B3] (Scheme 23). When replacing A5 with the more reactive aldehydes p-chlorobenzaldehyde A6 or by p-fluorobenzaldehyde A7, similar switching behavior were obtained in a relatively shorter time. The corresponding evolution of the 1 H NMR spectra, kinetic curves, and the Schemes for the two DCLs are displayed in experimental section (Figure III11 to Figure III 14, Scheme III12 and SchemeIII13). The evolution of the distributions of the two-component, threecomponent and four component mixtures were also shown in experiment part in TableIII1 to

Figure 82 .

 82 Figure 82. Evolution of 1 H NMR (400 MHz) spectra of the compounds generated from the DCL[1] mixture of equal amounts of A4, A5, B3, B4 (30 mM each in CD3CN, 25°C ) after 5 min, 25 min and 15 h (three bottom traces). The four top traces correspond to the isolated constituents A4B3, A4B4, A5B3 and A5B4. The arrows indicate the aldehyde CHO proton (9.5-10.0 ppm region) and the imine CH=N proton (8.0-8.5 ppm region) NMR signals of the compounds.

Figure 83 . 23 . 1 )Figure 86 ).Figure 84 . 1 H

 8323186841 Figure 83. (A). Kinetic curves of the compounds generated from a mixture of equimolar A4 + A5 + B3 + B4 as a function of time over 16 hours; (B). Zoom of (A). The composition % data have been obtained by integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ).

Figure 85 . 1 H

 851 Figure 85. 1 H NMR (400 MHz) spectra of the mixture of equimolar amount of A6, B3 and B4 (30 mM each, CD3CN, 25°C) after 5 min, 20 min, 3.5 h and 47 h (four bottom traces). The reference spectra of the isolated constituents A6B3 and A6B4 are shown above.

Figure 86 .

 86 Figure86.1 H NMR (400 MHz) spectra of the mixture of the same equivalent of A1, A6 and B3 (30 mM each, CD3CN, 25°C) after 5 minutes and 0.5 h (two bottom traces). The reference spectra of the isolated constituents A1B3 and A6B3 are shown above.

Figure 87 . 2 )Scheme 24 .Figure 88 .

 8722488 Figure 87. Kinetic plots of the evolution of a mixture of equimolar components (A). A1 + B3 + B4; (B). A6 + B3 + B4; (C). A1 + A6 + B3 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ). The kinetic curves are shown for only some of the compounds for clarity.

Figure 89 .

 89 Figure 89. Kinetic plots of the evolution of a mixture of equal amounts of components A1 + A6 + B3 + B4 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ). For clarity, the kinetic curves are shown for only some of the compounds.

  Instead of conducting the competitive experiment of the aldehyde A1 with the benzylamine B3 and N-methylbenzoylhydrazide B5, an easier way is to perform the competition set-up for [A1 + B4 + B5] to compare the kinetics and thermodynamic stabilities of the oxime A1B3 and acylhydrazone A1B5. Thus, the set-up were conducted in two different ratios with A1: B4: B5 = 1: 1: 1 and A1: B4: B5 = 2: 1: 1 see in the evolution of the 1 H NMR spectra from Figure 90 to Figure 91. The corresponding kinetic curves are shown in Figure 92.

Figure 90 . 1 H

 901 Figure 90. 1 H NMR (400 MHz) spectra of the mixture of the same equivalent of A1, B4 and B5 (30 mM each, CD3CN, 25°C) after 5 minutes, 162 h and 192 h (three bottom traces). The two top traces correspond to the isolated constituents A1B4 and A1B5.

Figure 91 .

 91 Figure 91. 1 H NMR (400 MHz) spectra of the mixture of 2.0 equiv. A1+ B4 + B5 (1.0 equiv. for B4 and B5) (30 mM each, CD3CN, 25°C) after 5 minutes, 53 h, 165 h and 222 h (from bottom to top). The reference spectra of the separately prepared constituents A1B4 and A1B5 is shown above.

Figure 92 .

 92 Figure 92. Kinetic plots of the evolution of the mixture of the three components: (A). A1 + B4 + B5 (1.0 equiv. for each); (B) 2.0 equiv. A1+ B4 + B5 (1.0 equiv. for B4 and B5) as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ). For clarity, the kinetic curves are shown for only some of the compounds.

Scheme 25 .Figure 93 .

 2593 Scheme 25. Kinetic switching of the [2 × 2] CDN formed by the DCL[3] set of components [A1 + A6 + B3 + B5] (top) from the [A1B3, A6 + B5] state (middle left) to the orthogonal state [A1B5, A6B3] (middle right) in CD3CN at 25°C. The indicated composition % values of the different compounds present correspond to reaction times of 5 min (left) and 96 h (right). Data obtained from the 400 MHz 1 H NMR spectra.

Figure 94 .

 94 Figure 94. Kinetic plots of the evolution of a mixture of equimolar A1 + A6 + B3 + B5 as a function of time. The composition % data have been obtained by integration of the imine -CH2-(of the benzyl group), hydrazone N-CH3 and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C ). For clarity, the kinetic curves are shown for some of the compounds.

Scheme 26 .Figure 95 .

 2695 Scheme 26. The [2 × 2] DCL formed by the DCL set of components [A1 + A4 + B3 + B5] in CD3CN at 25°C. Data obtained from the 400 MHz 1 H NMR spectra.

Figure 96 .

 96 Figure 96. Kinetic plots of the evolution of a mixture of equal amounts of components A1 + A4 + B3 + B5 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra (30 mM each, CD3CN, 25°C). For clarity, the kinetic curves are shown for only some of the compounds

Scheme 27 .

 27 Scheme 27. Evolution of a DCL of four ligand constituents undergoing a time-dependent switch of its associated [2 × 2] CDN driven by the formation of the complexes of two different metal cations M1 and M2.

Figure 97 .

 97 Figure 97. 1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A1 + A6 + B3 + B5 (30 mM each, CD3CN, 25°C) after 5 minutes, 96 h and 206 h (two bottom traces). The four top traces correspond to the isolated constituents A3B1, A3B3, A1B1 and A1B3.

Figure 98 . 1 H

 981 Figure 98. 1 H NMR (400 MHz) spectra of the mixture generated from equimolar amounts of A2 + A5 + B3 + B5 (30 mM each, CD3CN, 25°C ) adding Cu(I) after 5 minutes, adding Zn(II) after 5 minutes and heating at 60°C for 2 days. (three bottom traces). The reference spectra the isolated constituents A2B3, [Cu(A2B3)2] + , A2B5, [Zn(A2B5)2] 2+ , A5B3 and A5B5 are shown above.

Figure 99 . 1 H

 991 Figure 99. 1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A2 + A5 + B3 + B5 (30 mM each, CD3CN, 25°C) adding Cu(I) after 5 min, adding Fe(II) after 5 minutes and heating at 60°C for 2 days. (three bottom traces). The reference spectra of the isolated constituents A2B3, [Cu(A2B3)2] + , A2B5, [Fe(A2B5)2] 2+ , A5B3 and A5B5 are shown above.

Figure 100 . 1 HFigure 101 . 1 H

 10011011 Figure 100. 1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A2 + A5 + B3 + B5 (30 mM each, CD3CN, 25°C) adding Ag(I) after 3 hours, adding Zn(II) after 5 minutes and heating at 60°C for 2 days. (three bottom traces). The reference spectra of the isolated constituents A2B3, [Ag(A2B3)2] + , A2B5, [Fe(A2B5)2] 2+ , A5B3 and A5B5 are shown above.

  can be oxidized thus broadening the 1 H NMR spectra with the presence of B2. Therefore, only the two combination of metal cations were tested in the following experiment: 1) Ag(I) and Fe(II), 2) Ag(I) and Zn(II). 1) DCL[7] generated from the four components A2, A5, B2, B3 on sequential addition of Ag(I) and Fe(II) Firstly, equal amounts of the four components A2, A5, B2, B3 were mixed together to build up DCL[7]. Then 0.5 equivalent amount of Ag(I) was added immediately after the mixing. After about 1 hour, the amount of the Ag(I) complex of A2B3 increased as the main constituent in the DCL together with almost the same amount of the unreacted A5 and B2. Immediately after addition of Fe(II), the color of the solution changed to purple, likely due to the coordination of Fe(II) with B2. After heating at 60℃ for 2 days, there are some new peaks appearing which could be the hetero complexes of Fe(II) and [Fe(A2B2)2] 2+ . The aldehyde A5 still existed in a large amount indicating the very low reactivity of A5 with B2. This experiment demonstrated that the Fe(II) is still not a very excellent metal cation for coordinating with A2B2 to drive the formation of itself from the exchange reaction of [Ag(A2B3)2] + with B2.

Figure 102 . 1 H 7 ]

 10217 Figure 102. 1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A2 + A5 + B2 + B3 (30 mM each, CD3CN, 25°C) adding Ag(I) after 1 hour, adding Fe(II) after 5 minutes and heating at 60°C for 2 days. (three bottom traces). The four top traces correspond to the isolated constituents [Ag(A2B3)2] + , A5B3, A5B2 and [Fe(A2B2)2] 2+ .

Figure 103 . 1 H

 1031 Figure103.1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A2 + A5 + B2 + B3 (30 mM each, CD3CN, 25°C) after 5 minutes and 96 h (two bottom traces). The four top traces correspond to the isolated constituents A2B3, A2B2, A5B3 and A5B2.

Figure 104 . 1 H

 1041 Figure 104. 1 H NMR (400 MHz) spectra obtained from 1 H NMR titration experiment of B2 with different amounts of Zn(OTf)2.

Figure 105 .

 105 Figure 105. HRMS-ESI spectrum of [Zn(B2)2] 2+ obtained in situ from 2 equiv. B2 (20 mM) and 1 equiv. Zn(OTf)2 (10 mM) in CH3CN. Measured (top), simulated (bottom).

1 H

 1 Figure III32.

[Scheme 29 .

 29 Scheme 29. Kinetic switching of a [2 x 2] DCL[8] from the {[Ag(A2B1)2] + , A8 + B2} state to the orthogonal {[Zn(A2B2)2] 2+ , A8B1} state in CD3CN after 1 h at 25°C and 2 days at 25°C , then 60°C for 2 days (from left to right). Data obtained from the 500 MHz 1 H NMR spectra.

Figure 106 . 1 H

 1061 Figure106.1 H NMR (500 MHz) spectra of the DCL[8] mixture generated from equal amounts of A2 + A8 + B1 + B2 (10 mM each, CD3CN) ) + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 after 1 h at 25°C , 2 days at 25°C then 2 days at 60°C (three bottom traces). The four top traces correspond to the isolated constituents [Ag(A2B1)2] + , [Zn(A2B2)2] 2+ ,A8B1 and A8B2.

Figure 107 .Figure 108 . 1 H

 1071081 Figure 107. Kinetic plots of the evolution of the DCL[5] mixture of equal amounts of components A2 + A8 + B1 + B2 + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 500 MHz 1 H NMR spectra (10 mM each, CD3CN, 25°C).

2 (Scheme 30 .Figure 109 .

 230109 Scheme 30. Kinetic switching of the [2 × 2] CDN formed by the DCL[4] set of components [A1 + A8 + B1 + B2] (top) from the {[Ag(A1B1)2] + , [A8 + B2]} state (middle left) to the orthogonal state {[Zn(A1B2)2] 2+ , A8B1} (middle right) (in CD3CN at 25°C) after 1 h (left) and after 70 h (right). The indicated composition % values of the different compounds present correspond to reaction times of 1 h (left) and 70 h (right). Free anions are not indicated. Data obtained from the 500 MHz 1 H NMR spectra (Figure 109 and Figure 111).

Figure 110 .Figure 111 . 1 H

 1101111 Figure 110. Kinetic plots of the evolution of a mixture of equal amounts of components A1 + A8 + B1 + B2 (10 mM each) together with 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 as a function of time. The composition % data have been obtained by integration of the imine CH=N and aldehyde CHO proton signals in the 500 MHz 1 H NMR spectra (CD3CN, 25°C).

Figure 112 . 10 ]

 11210 Figure112.1 H NMR (500 MHz) spectra obtained from titration experiment of [Ag(A1B1)2] + and Zn(OTf)2. Reference spectra (top two traces) of the separately prepared constituents a) A1 + B1 + 0.5 equiv. Zn(OTf)2; b) A1 + B1 + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 c) A1 + A8 + B1 + B2 + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 after 1 h.

Figure 113 .Figure 114 .

 113114 Figure 113. Evolution of 1 H NMR (500 MHz) spectra of the compounds generated from the DCL10] mixture of equal amounts of A3, A8, B1, B2 (10 mM each in CD3CN, 25°C ) + 0.5 equiv. AgOTf (5 mM)+ 0.5 equiv. Zn(OTf)2 (5 mM) after 1 h at 25°C, 2 days at 25°C and heating at 60°C for 2 days (three bottom traces). The four top traces correspond to the isolated constituents [Ag(A3B1)2] + , [Zn(A3B2)2] 2+ , A8B1 and A8B2. The arrows indicate the aldehyde CHO proton (9.5-10.0 ppm region) and imine CH=N proton (8.0-8.5 ppm region) NMR signals of the compounds.

Scheme 32 .

 32 Scheme 32. Schematic time-dependent switching of a [2 × 2] DCL from kinetic distribution to the thermodynamic distribution with an orthogonal switching from one diagonal {AB, A'B'} to the other diagonal {AB', A'B]} of the square.

by 1 H

 1 NMR spectra, indicating that it's determined only by the internal kinetic and thermodynamic properties of the whole system.The present work explicitly implements networks switching driven by internal kinetic and thermodynamic properties in the self-contained CDNs. In terms of the constituent's amount, the very large amplification (from 3 to about 40 times) represents an adaptation to time, a significant step in the adaptive behavior of dynamic covalent systems. It paves the way to further exploration of kinetically adaptive behavior in CDC. The results described also bear relationship to the behavior of out-of-equilibrium systems opening towards higher level of kinetic behavior (for instance in training processes) in adaptive chemistry.

Scheme 33 .

 33 Scheme 33. Representation of the imine formation from PLP and Lysine (in enzyme) and the subsequent transamination processes.

Figure 116 .

 116 Figure 116. Structures of aldehydes tested for imine formation. The fraction of hydrated aldehyde is given in parentheses when it was detectable by 1 H NMR. Aldehydes 17-26 did not form detectable amounts of imines with aniline.

Figure 117 .

 117 Figure 117. Representation of the structures of aminoglycosides and aldehydes used for imine formation.

Scheme 35 .

 35 Scheme 35. Representation of the reactions of different aldehydes and amines to form imine from SALAL with IPA, cyclic aminal with PYRAL and diamine Me2PDA and lactone with CAXAL and a cyclic secondary amine PIP

Figure 118 .

 118 Figure 118. Reversible synthesis of fluorescent imine 3 from non-fluorescent amine 1 and weakly fluorescent aldehyde 2.

Figure 119 .

 119 Figure 119. (A). The beads on a string structure composed of nucleosomes; (B). The general composition structure unit of an octamer.

  evolutionary conservation indicates that a change in any position of the chain is deleterious to the cell. (N.B. a nucleosome = a histone octamer + DNA, Histone H1 can connect two nucleosome).

Figure 120 .

 120 Figure 120. The modification of histones through acetylation.

Figure 121 .

 121 Figure 121. Gene activation and repression are regulated by acetylation and deacetylation of core histones. Histone acetylation by coactivators that have intrinsic HAT activity, opened up the chromatin structure to allow binding of RNA polymerase II and transcription factors that were unable to bind DNA in the closed chromatin configuration. This is reversed by corepressors, which include HDACs that reverse this acetylation, causing gene silencing.

Figure 122 .

 122 Figure 122. The schematic catalysis of C=N formation from a pyridine-2-carboxaldehyde A1 (A2 or A3) and p-anisidine B1 in presence of metal salts catalyst.

Figure 124 .Figure 125 .

 124125 Figure 124. The pH titration experiment of PPAL (A4) with L1 in D2O at 25°C (5 mM each).

Figure 126 .

 126 Figure 126. The pH titration experiment of CAXAL with L1 in D2O at 25°C (5 mM each).

Figure 127 .

 127 Figure 127. The pH titration experiment of ASAL with L1 in D2O at 25°C (5 mM each).

Figure 128 .

 128 Figure 128. The pH titration experiment of SAXAL with L1 in D2O at 25°C (5 mM each).

40 .Scheme 40 .

 4040 Scheme 40.

Within 5

 5 minutes, there were about 38% of imine PLP-L1 formed together with less than 2% of hydrate of PLP observed in the spectra. After less than 1 hour, the composition of the reaction did not change any more, giving 62% of imine PLP-L1. The relative kinetic curves of the imine formation are shown in Figure 130A.

Figure 129 . 1 H

 1291 Figure 129. 1 H NMR (500 MHz) of the evolution of the imine formation from PLP and L1 (5 mM each, phosphate buffer, pH 11.0) at 25°C .

Figure 130 .

 130 Figure 130. The kinetic plot of the imine PLP-L1 and PLP-L2 formation from its components PLP and L1 or L2 (5 mM each, phosphate buffer, pH 11.0) at 25°C .

Figure 131 . 1 H

 1311 Figure131.1 H NMR (500 MHz) of the evolution of imine formation from PLP and L2 (5 mM each, phosphate buffer, pH 11.0) at 25°C .

  Figure132.1 H NMR (500 MHz) of the imine formation from PLP and L3 with the ratio of 1:1 (5 mM each, phosphate buffer, pH 11.0) at 25°C.The experiment of PLP and L3 were also conducted in the ratio of 2:1 in phosphate buffer (pH = 11.0) at 25℃ seen in Figure133. Similarly, the composition of the reaction did not change after 20 minutes. By adding one more equivalent of PLP, the yields of imines also increased. The final composition of the mixture included 21% PLP-ε-L3, 36% PLP-α-L3 and 22% of bisimine product PLP-α,ε-L3 together with free PLP and its hydrate. The total yield of imine according to the conversion of amino group is 79%.

Figure 133 . 1 H

 1331 Figure133.1 H NMR (500 MHz) of the imine formation from PLP and L3 with the ratio of 2:1 (5 mM each, phosphate buffer, pH 11.0) at 25°C.

Figure 134 . 1 H

 1341 Figure134.1 H NMR (500 MHz) of the imine formation from PLP and L3 with the ratio of 4:1 (5 mM each, phosphate buffer, pH 11.0) at 25°C .

Figure 135 . 1 H

 1351 Figure 135. 1 H NMR (500 MHz) of the imine formation from PLP and L4 (KKK) (5 mM each, phosphate buffer, pH 11.0) at 25°C .

Figure 136 . 1 H

 1361 Figure 136. 1 H NMR (500 MHz) of the imine formation from (5 mM) and L4 (15 mM) in phosphate buffer, at pH 11.0 at 25°C .

Figure 137 . 1 H

 1371 Figure 137. 1 H NMR (500 MHz) of the imine formation from PLP (5 mM) and L4 (20 mM) in phosphate buffer at pH 11.0 at 25°C .

Fluorochem

  and Adamas and were used without further purification. Deuterated solvents were purchased from Fluorochem or Sigma-Aldrich and used without further purification. Deionized water was obtained from a milli-gradient system (Millipore, France). Dry deuterated CD3CN was treated with 4Å molecular sieves. The molecular sieves were activated by heating at 550°C for 3 hours, then cool down progressively until 200°C, move the molecular sieves to a desiccator filled with argon.

to

  Nudelman et al. The CD3CN used for kinetics measurements of NMR was passed through molecular sieves to remove water and was preserved in a brown glass vial to keep out of the light. The quantitative 1 H NMR was measured by using HMDSO (hexamethyldisiloxane) as internal standard. The stock solution of HMDSO and components in CD3CN were prepared and added to the set of the experiments.

  -2-pyridinecarboxaldehyde (930 mg, 5.0 mmol) and phenylboronic acid (856 mg, 6.25 mmol) were dissolved in dioxane(36 mL) and water (4 mL) and flushed with nitrogen.Pd(PPh3)4 (290 mg, 0.25mmol) and Cs2CO3 (8.1 g, 25 mmol) were added. After refluxing overnight, water (100 mL) and CH2Cl2 (100 mL) were added to the solution after cooling to room temperature. The aqueous phase was separated and extracted with CH2Cl2 (25 mL), and the combined organic extracts were dried overnight using Na2SO4. Further purification by a silica gel column chromatography gave the title compound as a pale yellow oil, yield 68%.

(

  60 mM), the internal standard (hexamethyldisiloxane, 33.3 mM) and amine B1 (60 mM) or metal salt (60 mM) was prepared in advance. And then the same volume (100 μL) of Ax and By were mixed together with the internal standard (10 μL) and 100 μL B1 (or 5 uL for catalysis experiment) or 50 μL metal salt (or 5 uL for catalysis experiment) in CD3CN (600 μL). After vigorous shaking, the resulting mixture was monitored at 25°C by 1 H NMR as a function of time.

(

  60 mM) or hydrazine B2 (60 mM), metal salt (30 mM) and the internal standard (hexamethyldisiloxane, 33.3 mM) was prepared in advance. And then the same volume (100 μL) of Ax, B1 or B2 were mixed with 10 μL metal salt and the internal standard (10 μL) in CD3CN (600 μL). After vigorous shaking, the resulting mixture was monitored at 25°C by 1 H NMR as a function of time. ii. Characterization of the newly made compounds A3B1: 1 H NMR (500 MHz, CD3CN): δ = 8.54 (s, 1H, H 6 ), 8.13-8.11 (d, J = 10.0 Hz, 1H, H 2 ), 7.79-7.75 (t, J = 10.0 Hz, 1H, H 3 ), 7.63-7.61 (d, J = 10.0 Hz, 1H, H 4 ),

Figure II1. 1 H

 1 Figure II1. 1 H NMR spectrum of A3B1 (125 MHz, 298 K, CD3CN).

Figure II2. 13 C

 13 Figure II2.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A3B1 (125 MHz, 298 K, CD3CN).

Figure II3. 1 H

 1 Figure II3. 1 H NMR spectrum of A3B2 (125 MHz, 298 K, CD3CN).

Figure II4. 13 C

 13 Figure II4.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A3B2 (125 MHz, 298 K, CD3CN).

Figure II5. 1 H

 1 Figure II5. 1 H NMR spectrum of [Ag(A1B1)2] + (125 MHz, 298 K, CD3CN).

Figure II6. 13 C

 13 Figure II6. 13 C NMR spectrum of [Ag(A1B1)2] + (125 MHz, 298 K, CD3CN).

  ); ESI-MS: calculated for [C36H32N8+Zn] 2+ [CF3SO3] -789.1556, found: 789.1546. [C36H32N8+Zn] 2+ , found: 320.10.

Figure II7. 1 H

 1 Figure II7. 1 H NMR spectrum of [Zn(A1B2)2] 2+ (125 MHz, 298 K, CD3CN).

Figure II8. 13 C

 13 Figure II8.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of [Zn(A1B2)2] 2+ (125 MHz, 298 K, CD3CN).

[

  Ag(A2B1)2] + : 1 H NMR (500 MHz, CD3CN): δ = 8.97 (s, 1H, H 7 ), 8.05 (t, J = 10.0 Hz, 1H, H 4 ), 7.80 (d, J = 10.0 Hz, 1H, H 5 ), 7.60 (d, J = 10.0 Hz, 1H, H 3 ),

Figure II9. 1 H

 1 Figure II9. 1 H NMR spectrum of [Ag(A2B1)2] + (125 MHz, 298 K, CD3CN).

Figure II10. 13 C

 13 Figure II10. 13 C NMR spectrum of [Ag(A2B1)2] + (125 MHz, 298 K, CD3CN).

Figure II11. 1 H

 1 Figure II11. 1 H NMR spectrum of [Ag(A3B1)2] + (125 MHz, 298 K, CD3CN).

Figure II12. 13 C

 13 Figure II12. 13 C NMR spectrum of [Ag(A3B1)2] + (125 MHz, 298 K, CD3CN).

Figure II13. 1 H

 1 Figure II13. 1 H NMR spectrum of [Zn(A3B2)2] 2+ (125 MHz, 298 K, CD3CN).

Figure II14. 13 C

 13 Figure II14. 13 C NMR spectrum of [Zn(A3B2)2] 2+ (125 MHz, 298 K, CD3CN).

  [aldehyde chelate][amine] =kKeq[aldehyde][Zn(NCCH3)6 2+ ][amine],where Keq is the equilibrium constant for the preliminary complexation of the aldehyde. This is a rate law of the form R = k[Ax][By][C]

Figure II15 .

 II15 Figure II15. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the imine A1B1 formation from A1 + B1 (10 mM each) in CD3CN at 25°C over about 10% of the imine A1B1 formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II16 . 3 ) 2 Figure II17 . 4 )

 II1632II174 Figure II16. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the silver complex of imine [Ag(A1B1)]2 + formation from A1 + B1 (10 mM each) + 0.5 equiv. Ag (5 mM) in CD3CN at 25°C over about 10% of the silver complex of imine [Ag(A1B1)2] + formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II18 . 5 ) 6 )

 II1856 Figure II18. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the imine A2B1 formation from A2 + B1 (10 mM each) in CD3CN at 25°C over about 10% of the imine A2B1 formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II20 . 7 ) 8 )

 II2078 Figure II20. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the silver complex of imine [Ag(A2B1)]2 + formation from A2 + B1 + 0.5 equiv. AgOTf in CD3CN at 25°C over about 10% of the silver complex of imine [Ag(A2B1)]2 + formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II22 . 9 ) 2 Figure II23 . 1 ) 2 )

 II2292II2312 Figure II22. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of imine formation from A2 + B1 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C over the first 1 H NMR spectrum was obtained. The slope of the fit corresponds to the second order rate constant. NOTE: The reaction of A2 + B1 in presence of 0.5 equiv. Zn(OTf)2 is already complete within 5 minutes (the time to insert the tube, lock, shim and run the acquisition), the rate constant (k ≥ 18.5 M -1 s -1 ) is the lowest value, which is calculated from the first 1 H NMR spectrum obtained.

Figure II26 . 4 ) 5 )

 II2645 Figure II26. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone [Zn(A1B2)2] 2+ formation from (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C over about 10% of the zinc complex of hydrazone [Zn(A1B2)2] 2+ formation. The slope of the fit corresponds to the second order rate constant; R2 values shown.

Figure II28 .

 II28 Figure II28. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the hydrazone A3B2 formation from A3 + B2 (10 mM each) in CD3CN at 25°C over about 10% of the hydazone A3B2 formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II32 . 1 )Figure II33 .

 II321II33 Figure II32. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone [Zn(A3B2)2] 2+ formation from A3 + B2 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C over about 10% of the zinc complex of hydrazone [Zn(A3B2)2] 2+ formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II34 . 3 ) 2 aFigure II35 .Figure II36 .Figure II37 .Figure II38 . 4 )Figure II39 . 5 )Figure II40 .

 II3432II35II36II37II384II395II40 Figure II34. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the hydrazone-based silver complex [Ag(A1B2)2] + formation from A1 + B2 + B1 (10 mM each) + 0.5 equiv. AgOTf (5 mM) in CD3CN at 25°C over about 10% of the silver complex of hydazone [Ag(A1B2)2] + formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II44 . 1 )

 II441 Figure II44. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone [Zn(A3B2)2] 2+ formation from A3 + B2 + B1 (10 mM each) + Zn(OTf)2 (5 mM) in CD3CN at 25°C over about 10% of the zinc complex of hydrazone [Zn(A3B2)2] 2+ formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II46 . 3 )

 II463 Figure II46. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the imine A1B1 formation from A1 + B1 (10 mM each) + 0.05 equiv. AgOTf (0.5 mM) in CD3CN at 25°C over about 10% of the imine A1B1 formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II50 . 4 ) 3 Figure II51. 1 H

 II50431 Figure II50. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the imine A1B1 formation from A1 + B1 (10 mM each) + 0.05 equiv. CF3COOD (0.5 mM) in CD3CN at 25°C over the first 1 H NMR spectrum was obtained. The slope of the fit corresponds to the second order rate constant; R 2 values shown. NOTE: The reaction of A1 + B1 in presence of 0.05 equiv. CF3COOD is already finished in 3 minutes, the rate constant (k ≥ 6.3 M -1 s -1 ) is the lowest value, which is calculated from the first 1 H NMR spectrum obtained.

Figure II52 . 5 )

 II525 Figure II52. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the imine A1B1 formation from A1 + B1 (10 mM each) + 0.05 equiv. Sc(OTf)3 (0.5 mM) in CD3CN, 25°C over the first 1 H NMR spectrum was obtained. The slope of the fit corresponds to the second order rate constant; R 2 values shown. NOTE: The reaction of A1 + B1 in presence of 0.05 equiv. Sc(III) is already finished in 3 minutes, the rate constant (k ≥ 13 M -1 s -1 ) is the lowest value, which is calculated from the first 1 H NMR spectrum obtained.

Figure II54 . 6 ) 2 Figure II55. 1 H

 II54621 Figure II54. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the hydrazone A1B2 formation from A1 + B2 (10 mM each) + 0.5 equiv. AgOTf (0.5 mM) in CD3CN at 25°C over about 10% of the hydrazone A1B2 formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II56 .

 II56 Figure II56. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone A1B2 formation from A1 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2 (0.5 mM) in CD3CN at 25°C over about 10% of the hydrazone A1B2 formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

Figure II60. 1 HFigure II61 . 9 )

 1II619 Figure II60.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 (10 mM each) + 0.5 equiv. Sc(OTf)3 (0.5 mM) in CD3CN at 25°C after 5 min, 25 min, 3 h from bottom to top. Reference spectrum of the separately prepared constituent A1B2.

Figure II64. 1 HFigure II65 .

 1II65 Figure II64.1 H NMR (500 MHz) spectra of the mixture generated from equal amounts of A1 + B2 (10 mM each) + 0.05 equiv. Zn(OTf)2 (0.5 mM) + 0.05 equiv. B1 (0.5 mM) after in CD3CN at 25°C after 5 min, 10.5 h, 45 h from bottom to top. Reference spectra (top two traces) of the separately prepared constituents A1B2, [Zn(A1B2)2] 2+ .

  65.03(C 11 ) ESI-MS: calculated for [C19H16N2+H] + 273.1392, found, 273.1382; Elemental analysis calculated (%) for C19H16N2: C, 83.79; H, 5.92; N, 10.29; found: C, 83.34; H, 5.93; N, 10.25.

Figure III1. 1 H

 1 Figure III1. 1 H NMR spectrum of A1B3 (500 MHz, 298 K, CD3CN).

Figure III2. 13 C

 13 Figure III2.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A1B3 (125 MHz, 298 K, CD3CN).

Figure III3. 1 H

 1 Figure III3. 1 H NMR spectrum of A1B4 (500 MHz, 298 K, CD3CN).

Figure III4. 13 C

 13 Figure III4.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A1B4 (125 MHz, 298 K, CD3CN).

Figure III5. 1 H

 1 Figure III5. 1 H NMR spectrum of A1B5 (500 MHz, 298 K, CD3CN).

Figure III6. 13 C

 13 Figure III6.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A1B5 (125 MHz, 298 K, CD3CN).

Figure III7. 1 H

 1 Figure III7. 1 H NMR spectrum of A7B4 (500 MHz, 298 K, CD3CN).

Figure III8. 13 C

 13 Figure III8.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A7B4 (125 MHz, 298 K, CD3CN).

Figure III9. 1 H

 1 Figure III9. 1 H NMR spectrum of A8B2 (500 MHz, 298 K, CD3CN).

Figure III10. 13 C

 13 Figure III10.[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR spectrum of A8B2 (125 MHz, 298 K, CD3CN).

1 )

 1 DCL generated from A1 + A6 + B3 + B5.

Figure III11. 1 H

 1 Figure III11.1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A4 + A6 + B3 + B4 (30 mM each, CD3CN, r.t.) after 5 minutes, 30 minutes and 24 h (from bottom to up). The top four traces are the reference spectra of the separately prepared constituents A4B3, A4B4, A6B3 and A6B4.

Figure III12 .

 III12 Figure III12. Kinetic plots of the evolution of a mixture of equal amounts of components A4 + A6 + B3 + B4 as a function of time as obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra(30 mM each, CD3CN, r.t.). For clarity, the kinetic curves are shown for only some of the compounds.

  Scheme III2. Kinetic switch of a [2 × 2] DCL from the [A4B3, A6 + B4] state to the orthogonal state [A4B4, A6B3] in CD3CN at room temperature. Data obtained from the 400 MHz 1 H NMR spectra.

4 )

 4 Figure III13.1 H NMR (400 MHz) spectra of the mixture generated from equal amounts of A4 + A7 + B3 + B4 (30 mM each, CD3CN, r.t.) after 5 min, 10 min, 3 h (from bottom to up). The top four traces are the reference spectra of the separately prepared constituents A4B3, A4B4, A7B3 and A7B4.

Figure III14 .

 III14 Figure III14. Kinetic plots of the evolution of the mixture of equal amounts of components A4 + A7 + B3 + B4 as a function of time obtained from integration of the imine CH=N and aldehyde CHO proton signals in the 400 MHz 1 H NMR spectra(30 mM each, CD3CN, r.t.). For clarity, the kinetic curves are shown for only some of the compounds.

  Scheme III3. Kinetic switch of a [2 × 2] DCL from the [A4B3, A7 + B4] state to the orthogonal state [A4B4, A7B3] in CD3CN at room temperature. Data obtained from the 400 MHz 1 H NMR spectra.

5 )

 5 DCL generated from equal amounts of A1 + A6 + B3 + B4

Figure III15. 1 H

 1 Figure III15.1 H NMR (600 MHz) spectra of the mixture generated from equal amounts of A1 + A8 + B1 + B2 (10 mM each, CD3CN) + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 after 1 h (bottom) and 70 hours (top) at 25°C .

Figure III17. 1 H

 1 Figure III17.1 H NMR (600 MHz) spectra of the mixture generated from equal amounts of A3 + A8 + B1 + B2 (10 mM each, CD3CN) + 0.5 equiv. AgOTf + 0.5 equiv. Zn(OTf)2 after 1 hour (bottom), and after heating 2 days (top).

4 )

 4 HRMS-ESI spectra of Zinc (II) complex [Zn(B2)2] 2+ of B2.

Figure III18 .

 III18 Figure III18. HRMS-ESI spectrum of [Zn(B2)2] 2+ obtained in situ from 3 equiv. B2 (30 mM) and 1 equiv. Zn(OTf)2 (10 mM) in CH3CN. Measured (top), simulated (bottom).

Figure III19. 1 H

 1 Figure III19.1 H NMR (500 MHz) spectra of A1, A1+0.5 equiv. AgOTf, A1+0.5 equiv. Zn(OTf)2 and A1+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A1 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III20. 1 H

 1 Figure III20.1 H NMR (500 MHz) spectra of A8, A8+0.5 equiv. AgOTf, A8+0.5 equiv. Zn(OTf)2 and A8+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A8 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III21. 1 H

 1 Figure III21.1 H NMR (500 MHz) spectra of A2, A2+0.5 equiv. AgOTf, A2+0.5 equiv. Zn(OTf)2 and A2+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A2 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III22. 1 H

 1 Figure III22.1 H NMR (500 MHz) spectra of A3, A3+0.5 equiv. AgOTf, A3+0.5 equiv. Zn(OTf)2 and A3+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A3 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III23. 1 H

 1 Figure III23.1 H NMR (500 MHz) spectra of B1, B1+0.5 equiv. AgOTf, B1+0.5 equiv. Zn(OTf)2 and B1+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for B1 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III24. 1 H

 1 Figure III24.1 H NMR (500 MHz) spectra of B2, B2+0.5 equiv. AgOTf, B2+0.5 equiv. Zn(OTf)2 and B2+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for B2 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III25. 1 H

 1 Figure III25.1 H NMR (500 MHz) spectra of A1B1, A1B1+0.5 equiv. AgOTf, A1B1+0.5 equiv. Zn(OTf)2 and A1B1+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A1B1 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III26. 1 H

 1 Figure III26.1 H NMR (500 MHz) spectra of A1B2, A1B2+0.5 equiv. AgOTf, A1B2+0.5 equiv. Zn(OTf)2 and A1B2+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A1B2 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III27. 1 H

 1 Figure III27.1 H NMR (500 MHz) spectra of A2B1, A2B1+0.5 equiv. AgOTf, A2B1+0.5 equiv. Zn(OTf)2 and A2B1+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A2B1 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III28. 1 H

 1 Figure III28.1 H NMR (500 MHz) spectra of A2B2, A2B2+0.5 equiv. AgOTf, A2B2+0.5 equiv. Zn(OTf)2 and A2B2+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A2B2 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III29. 1 H

 1 Figure III29.1 H NMR (500 MHz) spectra of A3B1, A3B1+0.5 equiv. AgOTf, A3B1+0.5 equiv. Zn(OTf)2 and A3B1+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A3B1 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III30. 1 H

 1 Figure III30.1 H NMR (500 MHz) spectra of A3B2, A3B2+0.5 equiv. AgOTf, A3B2+0.5 equiv. Zn(OTf)2 and A3B2+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A3B2 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III31. 1 H

 1 Figure III31.1 H NMR (500 MHz) spectra of A8B1, A8B1+0.5 equiv. AgOTf, A8B1+0.5 equiv. Zn(OTf)2 and A8B1+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A8B1 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

Figure III32. 1 H

 1 Figure III32.1 H NMR (500 MHz) spectra of A8B2, A8B2+0.5 equiv. AgOTf, A8B2+0.5 equiv. Zn(OTf)2 and A8B2+0.5 equiv. AgOTf +0.5 equiv. Zn(OTf)2 obtained from freshly mixing the components in CD3CN at r.t. The concentration for A8B2 is 10 mM and for AgOTf or Zn(OTf)2 is 5 mM.

1 )

 1 Procedures for preparation of the phosphate buffer 0.134 g of Na2HPO4.7H2O (M = 268.07) was dissolved in approx. 9 ml of D2O and then titrated to pH 11.39 at the lab temperature of 25 o C with monovalent strong base (NaOD) or acid (DCl) as needed. The volume of D2O was made up to 10 ml with pure water, the buffer was ready with pH 11.4 at 25 o C.

Figure S2 .

 S2 Figure S2. Crystal structure for [Ag(A3B1)2] + and [Zn(A1B2)2] 2+ .

Final

  thèse, nous avons exploré la formation de composés C=N: la cinétique et la catalyse de la formation C=N, la commutation en fonction du temps de bibliothèques covalentes dynamiques ainsi que la formation d'imine améliorée en phase aqueuse. Premièrement, la formation d'imine et d'hydrazone a été fortement accélérée en présence de sels métalliques comme catalyseurs. Le fonctionnement simultané de l'amine et des sels métalliques a montré une catalyse synergique sur la formation d'hydrazone. Deuxièmement, les[2 × 2] DCL réalisent un passage en fonction du temps de la distribution cinétique à la distribution thermodynamique en criblant les composants à la fois en l'absence et en présence de deux sels métalliques Ag (I) et Zn (II). Troisièmement, du point de vue thermodynamique, la formation d'imine en phase aqueuse a été grandement améliorée en ajustant différents facteurs pour accélérer et stabiliser les produits d'imine générés. MOTS-CLÉS : Chimie dynamique constitutionnelle, Chimie covalente dynamique, Bibliothèques covalentes dynamiques, États hors équilibre, Commutation cinétique de DCL

  La nature a toujours été une source d'inspiration pour les scientifiques. La capacité des organismes vivants à s'adapter à leurs environnements a inspiré de nombreux chimistes à développer des systèmes chimiques artificiels, capables d'un comportement adaptatif envers des stimuli physiques ou chimiques. La caractéristique commune de tous ces systèmes est leur nature dynamique. Ainsi, la Chimie Adaptative, qui les étudie, repose sur deux piliers principaux : (i) la chimie supramoléculaire, qui enveloppe les interactions non covalentes, intrinsèquement dynamiques; et (ii) la Chimie Covalente Dynamique (DCvC, référant à Dynamic Covalent Chemistry), qui enveloppe les liaisons covalentes réversibles. La chimie supramoléculaire et la DCvC établissent ensemble la Chimie Dynamique Constitutionnelle

	pH Phe RESUME EN FRANCAIS Potential of Hydrogen Phenylalanine
	D RNA Ala SDS CDC  CDLs Val	Ribonucleic Acid Acceptor-Donor-Acceptor Sodium Dodecyl Sulfate Alanine Millimolar, 10 -3 mol L -1 Constitutional Dynamic Chemistry Constitutional Dynamic Libraries Valine
	CDNs	Constitutional Dynamic Networks
	C=N	Imine Compound
	CMC	Critical Micelle Concentration
	DNCC	Dynamic Non-Covalent Chemistry
	DCRs	Dynamic Covalent Reactions
	DNA	Deoxyribonucleic Acid
	DD	Donor-Acceptor-Donor
	EDG	Electro-Donating Group
	EWG	Electro-Withdrawing Group
	Equiv.	Equivalent
	ESI	Electro Spray Ionization
	Gly	Glycine
	h	Hour
		Highest Occupied Molecular Orbital
	s	Histone Acetyltransferase
	Ds	Histone Deacetylase
	HMDSO	Hexamethyldisiloxane
	HRMS	High Resolution Mass Spectroscopy
	His	Histidine
	k	Rate Constant
	LUMO	Lowest Unoccupied Molecular Orbital
	min	Minute
	NMR	Nuclear agnetic Resonance
	NBI	Naphthalene Bisimide
	mM	Millimolar per Liter
	OTf	Trifluoromethanesulfonate
	OEG	Oligoethylene Glycol
	PLP	Pyridoxal Phosphate
	ppm	Part per Million
		xiii xiv

(CDC, référant à Constitutional Dynamic Chemistry). La CDC étudie les systèmes qui subissent des changements constitutionnels par échange de composants grâce à la mise en oeuvre de réactions covalentes réversibles et/ou d'interactions non covalentes. De tels systèmes sont souvent appelés Bibliothèques Dynamiques Constitutionnelles (CDLs, référant à Constitutional Dynamic Libraries) ou Réseaux (CDNs, référant à Constitutional Dynamic Networks). Ces dernières années, des nombreuses études ont été effectuées sur les CDLs dans les

Table 1 .

 1 Comparison of different noncovalent interactions.[START_REF] Hoeben | About Supramolecular Assemblies of π-Conjugated Systems[END_REF][START_REF] Osypenko | Supramolecular Self-assemblies of Triarylamines: Fundamental Studies and Applications[END_REF]

	Interaction	Strength, kJ/mol	Example
	Ion-ion	200 -300	(n-Bu)4N + Cl -
	Ion-dipole	50 -200	Sodium and [15] crown-5
	Dipole-dipole	5 -50	Acetone
	Hydrogen bonding	4 -120	Nucleotides within DNA
	Cation-π	5 -80	K + in benzene
	π-π	0 -50	Benzene and graphite
	Van der Waals	<5 (but variable depending on surface area)	Liquid gases, packing in molecular crystals
	Hydrophobic	Related to solvent-solvent interaction energy	Cyclodextrin inclusion compounds
	Metal-ligand	0 -400	Zn(NH3)4 2+

  1

  C with amplification of the latter. Thus, this CDL underwent orthogonal dual adaptation via component exchange in response to two external effectors: metal cation (a chemical effector)

Table 2 .

 2 The dynamic covalent reactions used in DCC.

	Bond type	Reactions	Structure	References
		Aldol formation		105-107
	Dynamic C-C bond	Diels-Alder reaction		108-110
		Olefin metathesis		111
		Ester		15,112,113
	Dynamic	formation/exchange
	C-O bond	Acetal		114-117
		formation/exchange
	Dynamic	Disulfide formation		118-121
	S-S bond	Disulfide exchange		122,123
		C=N formation		124-127
	Dynamic	Aminal formation		128-130
	C-N bond
		Transimination		131-133
		Imine metathesis		67,134-136
		Knoevenagel		137-140
		exchange
	For dynamic C-N bond, it includes: (i) C=N formation; (ii) transamination; (iii) imine
	metathesis. The mechanism as well as the catalysis of the reactions were discussed in the
	following in details.

Table 3 .

 3 catalysis of C=N bond formation (imine, hydrazone, oxime)

	Bond type	Catalysts	References
	C=N formation
	(imine, oxime,

Table 4 .

 4 Kinetic features of the reactions between aldehyde A1, A2 or A3 and p-anisidine B1 in the absence and presence of metal salts.

	Entry

[a] Reaction Catalyst 0.5 equiv. Product t50[h] [c] t10[h] [d] k [e] / 10 -3 M -1 s -1 Acceleration Factor

	1	A1 + B1	_ [b]	A1B1	23	3	1.1	n.a. [f]
	2	A1 + B1 + Ag(I)	Ag(I)	[Ag(A1B1)2] +	1.4	0.5	20	18
	3	A1 + B1 + Zn(II)	Zn(II)	[Zn(A1B1)2] 2+	≤0.08	≤0.08	≥18200	≥16500
	4	A2 + B1	_ [b]	A2B1	48	6.5	0.64	n.a. [f]
	5	A2 + B1 + Ag(I)	Ag(I)	[Ag(A2B1)2] +	1.9	0.27	14	22
	6	A2 + B1 + Zn(II)	Zn(II)	[Zn(A2B1)2] 2+	≤0.08	≤0.08	≥18500	≥28900
	7	A3 + B1	_ [b]	A3B1	2.1	0.3	12	n.a. [f]
	8	A3 + B1 + Ag(I)	Ag(I)	[Ag(A3B1)2] +	0.80	0.08	44	4
	9	A3 + B1 + Zn(II)	Zn(II)	[Zn(A3B1)2] 2+	≤0.08	≤0.08	≥33000	≥2750

- 3 M -1 s -1

								Acceleration
								Factor
	1	A1 + B2	No catalyst	A1B2	21	1.94	0.97	n.a. [f]
	2	A1 + B2 + Ag(I) Ag(I)	[Ag(A1B2)2] +	2.4	0.35	14	14
	3	A1 + B2 + Zn(II) Zn(II)	[Zn(A1B2)2] 2+	4	0.55	7.5	8
	4	A1 + B2 + B1	B1 (1.0 equiv.) A1B2	8.8	0.97	2.4	3
	5	A1 + B2 + B1 + Ag(I)	B1 (1.0 equiv.) + Ag(I)	[Ag(A1B2)2] +	2.7	0.44	16	16
	6	A1 + B2 + B1 + Zn(II)	B1 (1.0 equiv.) + Zn(II)	[Zn(A1B2)2] 2+	0.15	≤0.08	≥610	630
	7

Table 7 .

 7 Kinetic features of the reactions between aldehyde A2 and hydrazine B2 in the absence and presence of metal salts separately as well as in presence of both B1 and metal salts together

	Entry [a]	Reaction [b]	Catalyst	Product	t50[h] [c]	t10[h] [d]	k [e] /10 -3 M -1 s -1	Acceleration Factor
	1	A2 + B2	__ [b]	A2B2	37	3.9	0.57	n.a. [f]
	2	A2 + B2 + Ag(I)	Ag(I)	[Ag(A2B2)2] +	2.8	0.38	11	19
	3	A2 + B2 + Zn(II)	Zn(II)	[Zn(A2B2)2] 2+ 5.1	0.98	11	19
	4	A2 + B2 + B1	B1	A1B2	14	2.9	1.7	3
	5	A2 + B2 + B1 + Ag(I)	B1 +Ag(I) [Ag(A1B2)2] +	4.1	1.4	8.8	15
	6	A2 + B2 + B1 + Zn(II)	B1+Zn(II) [Zn(A1B2)2] 2+ 0.26	0.07	240	≥421

Table 9 .

 9 Kinetic features of the reactions between aldehyde A1 and p-anisidine B1 or hydrazine B2 in absence and in presence of catalysts

	Entry [a]	Reaction	Catalyst 0.05 eq.	t50[h] [c]	t10[h] [d]	k [e] / M -1 s -1	Acceleration factor	TOF/h -1
	1	A1+B1	_ [b]	23	3	1.1×10 -3	1	n.a. [f]
	2	A1+B1	Ag(I)	35	2.2	1.6×10 -3	1.5	0.005
	3	A1+B1	Zn(II)	< 4 min	< 4 min	2.9	2.6×10 3	>8.3
	4	A1+B1	Sc(III)	< 4 min	< 4 min	> 6.3×10 3	5.7×10 6	>181
	5	A1+B1	CF3COOD	< 4 min	< 4 min	> 1.3×10 4	1.2×10 7	306
	6	A1+B2	_ [b]	21	1.9	0.97×10 -3	1	n.a. [f]
	7	A1+B2	Ag(I)	6.2	1.5	2.8×10 -3	3	0.98
	8	A1+B2	Zn(II)	6.4	1.7	2.1×10 -3	2	0.54
	9	A1+B2	Sc(III)	0.15	< 4 min	> 0.117	>121	6.5
	10	A1+B2	CF3COOD	0.17	< 4 min	>4.6×10 -2	>47	3.5
	11	A1+B2	Zn(II)+ B1	7.7	1.5	6×10 -3	6	0.60
	12	A2+B2	Zn(II)	5	0.8	2.9×10 -3	3	0.44

Table 10 .

 10 Distribution of imines generated by reaction of different aldehydes with N-α-acetyl lysine at pH values of7.4, 8.1, 11.0 at 25℃ in D2O (in phosphate buffer), using an initial concentration of 20 mM for all reactants at 25℃.

	Entry	Aldehyde	Product	pH = 7.4	pH = 8.1	pH = 11.0
			Aldehyde or amine	58%	n.d.	15%
	1		Imine	29%	n.d.	69%
		PLP	Hydration	13%	n.d.	17%
			Aldehyde or amine	85%	81.7%	38%
	2		Imine	1%	4.3%	56%
		DSBAL	Hydration	14%	14.0%	6%
			Aldehyde or amine	97%	95.7%	49%
	3		Imine	_ [a]	_ [a]	51%
		OSBAL	Hydration	3%	3.3%	_ [a]
			Aldehyde or amine	95%	92%	49%
	4	SFAL	Imine	_ [a]	3%	49%
			Hydration	5%	5%	2%
			Aldehyde or amine	60%	59%	34%
	5		Imine	_ [a]	1.0%	46%
		OPAL	Hydration	40%	40%	19%
			Aldehyde or amine	n.d.	38%	26%
	6		Imine	n.d.	8%	44%
		PPAL	Hydration	n.d.	54%	29.8%
			Aldehyde or amine	n.d.	88%	58%
	7		Imine	n.d.	_ [a]	37%
		MPAL	Hydration	n.d.	12%	5%
			Aldehyde or amine	100%	100%	83%
	8		Imine
		MSBAL

Table 11 .

 11 Distribution of the reactions of imine formation generated from equimolar PLP and amines with different hydrophobic groups at pH 8.1 at 25℃ in D2O (in phosphate buffer), using an initial concentration of 5 mM for all reactants at 25℃.

						Other side
	Entry [a]	Amine	pKa	Imine	Aldehyde	products (hydrate +
						hemiaminal)
	1		10.78	32%	29%	39%
	2		9.33	55%	35%	10%
	3		-	64%	27%	9%
	4		10.2	10%	12%	78%
	5		n.d.	n.d.	n.d.	n.d.

  The pH titration experiment of PLP with L1 in D2O at 25°C (5 mM each).

	PLP		SAXAL	OPAL		PPAL	ASAL	CAXAL
	PLP			SAXAL	OPAL		PPAL	ASAL	CAXAL
	65%			50%	50%		40%	30%	16%
	at pH = 10.5
	Figure 123.	Conversion to imine [%]	20 40 60 80	PLP SAXAL PPAL CAXAL ASAL OPAL
			0
			2	4	6	8	10	12
					pH

  ); ESI-MS: calculated for [C13H11BrN2O+H] + 291.0128, found: 291.0123; Elemental analysis calculated (%) for C13H11BrN2O: :C, 53.63; H, 3.81; Br, 27.44; N, 9.62; O, 5.50; found: C, 53.53; H, 3.85; N, 9.55.

  C NMR (126 MHz, CD3CN): δ161.24 (C 10 ), 155.80 (C 6 ), 152.51 (C 1 ), 143.59,(C 5 ) 142.28 (C 3 ), 140.86 (C 7 ), 132.01 (C 4 ), 127.27 (C 2 ), 125.01 (C

6 )

 6 Kinetics of A2 + B2 in presence of AgOTf Figure II29. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the silver complex of hydrazone [Ag(A2B2)2] + formation from A2 + B2 (10 mM each) + 0.5 equiv. of AgOTf (5 mM) in CD3CN at 25°C over about 10% of the silver complex of hydazone [Ag(A2B2)2] + formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown. Kinetics of A2 + B2 in presence of Zn(OTf)2 Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone [Zn(A2B2)2] 2+ formation from A2 + B2 (10 mM each) + 0.5 equiv. of Zn(OTf)2 (5 mM) in CD3CN at 25°C over about 10% of the zinc complex of hydrazone [Zn(A2B2)2] 2+ formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown.

	8) Figure II31.	1/[A t ]-1/[A 0 ] / M	0 50 100 150 200	0	4000 y = 1.1 × 10 -2 8000 Time [Sec] R 2 = 0.995	12000	16000
			250
			200
		0 ] / M t ]-1/[A	100 150		y = 1.3 × 10 -2 R 2 = 0.993
		1/[A
			50
			0
				0	4000	8000	12000	16000
						Time [Sec]
	Figure II30. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the silver complex of
	hydrazone [Ag(A3B2)2] + formation from A3 + B2 (10 mM each) + 0.5 equiv. of AgOTf (5 mM) in CD3CN
	at 25°C over about 10% of the silver complex of hydrazone [Ag(A3B2)2] + formation. The slope of the fit
	corresponds to the second order rate constant; R 2 values shown.

7)

Kinetics of A3 + B2 in presence of AgOTf 9) Kinetics of A3 + B2 in presence of Zn(OTf)2

6 )

 6 Kinetics of A2 + B2 in presence of both B1 and AgOTf FigureII41. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the silver complex of hydrazone [Ag(A2B2)2] + formation from A2 + B2 + B1 (10 mM each) + 0.5 equiv. AgOTf (5 mM) in CD3CN at 25°C over about 10% of the silver complex of hydrazone [Ag(A2B2)2] + formation. The slope of the fit corresponds to the second order rate constant; R 2 values shown. Kinetics of A2 + B2 in presence of both B1 and Zn(OTf)2 Zn(OTf)2 (5 mM) in CD3CN at 25°C over about 10% of the zinc complex of hydrazone [Zn(A2B2)2] 2+ formation. The slope of the fit corresponds to the second order rate constant; R 2 value shown.

	0 8) Figure II43. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone 4000 8000 12000 16000 0 40 80 120 1/[A t ]-1/[A 0 ] / M Time [Sec] y = 8.8 × 10 -3 R 2 = 0.994
	[Zn(A2B2)2]
		300
		250
	1/[A 0 ] / M t ]-1/[A	100 150 200	y = 2.3 × 10 -2 R 2 = 0.96
		50
		0
		0	2000 4000 6000 8000 10000 12000
			Time [Sec]
	Figure II42. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the silver complex of
	hydrazone [Ag(A3B2)2] + formation from A3 + B2 + B1 (10 mM each) + AgOTf (5 mM) in CD3CN at 25°C
	over about 10% of the silver complex of hydrazone [Ag(A3B2)2] + formation. The slope of the fit
	corresponds to the second order rate constant; R 2 values shown.

7)

Kinetics of A3 + B2 in presence of both B1 and AgOTf 2+ formation from A2 + B2 + B1 (10 mM each) + 9) Kinetics of A3 + B2 in presence of both B1 and Zn(OTf)2

7 )

 7 Kinetics of A2 + B2 in presence of 0.05 equiv. Zn(OTf)2

	Figure II59. Representative linear least-squares fit (1/[A]t -1/[A]0 vs. t) of the zinc complex of hydrazone
	A2B2 formation from A1 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2 (0.5 mM) in CD3CN at 25°C over
	about 10% of the hydrazone A2B2 formation. The slope of the fit corresponds to the second order rate
	constant; R 2 values shown.
	0 Figure II57. Figure II58. Formation of hydrazone A2B2 from a mixture of equal amounts of components A2 + B2 10 20 30 40 50 60 0 20 40 60 80 100 A2 B2 A2B2 [Zn(A2B2) 2 ] 2+ Composition [%] Time [h]
	(10 mM each) + 0.5 equiv. Zn(OTf)2 (0.5 mM) in CD3CN at 25°C as a function of time as obtained from
	integration of the imine CH=N proton signal in the 500 MHz 1 H NMR spectra.

1

H NMR (500 MHz) spectra of the mixture generated from equal amounts of A2 + B2 (10 mM each) + 0.5 equiv. Zn(OTf)2 (0.5 mM) in CD3CN at 25°C after 5 min, 8.4 h, 34 h, 58 h from bottom to top. Reference spectra (top two traces) of the separately prepared constituents A2B2, [Zn(A2B2)2] 2+ .

8)

Kinetics of A1 + B2 in presence of 0.05 equiv. of Sc(OTf)3

  1 H NMR (500 MHz, CD3CN, 298 K): δ = 8.55 (s, 1H, H 10 ), 8.14-8.06 (m, 2H, H3,3' ), 7.96-7.95 (t, 1H, H 7 ), 7.93-7.82 (m, 2H, H 6+8 ), 7.56-7.49 (m, 2H, H 2,2' ), 7.49-7.43 (m,

  A1B4:1 H NMR (500 MHz, CD3CN): δ = 8.27 (s, 1H, H 10 ),8.10-8.01 (m, 2H, H 3,3' ), 7.88-7.80 (m, 2H, H 6+8 ), 7.79-7.70 (m, 1H, H 7 ), 7.53-7.47 (m, 2H, H 2,2' ),7.47-7.43 (m, 3H, H 1+13,13' ), 7.42-7.37 (m, 2H, H 14,14' ),7.37-7.30 (m, 1H, H 15 ), 5.25 (s, 2H, H 7 ).[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR (126MHz, CD3CN): δ 157.44(C 5 ), 152.11(C 9 ), 150.78(C 10 ), 139.29(C 4 ), 138.37(C 12 ), 138.36(C 6 ), 129.93 (C 1 ), 129.43(C

  A1B5:1 H NMR (500 MHz, CD3CN): δ = 8.12-8.05(m, 2H, H 3,3' ), 7.96 (s, 1H, H 10 ), 7.79-7.77 (dd, J = 10.0, 5.0 Hz, 1H, H 6 ), 7.74 (t, J = 7.7 Hz, 1H, H 7 ),7.72-7.66 (m, 2H, H 14,14' ),

  C NMR (126 MHz, CD3CN): δ 171.36(C 12 ), 157.13(C 5 ), 154.59(C 9 ), 140.95(C 10 ), 139.36(C 4 ), 138.27(C 7 ), 136.29(C 13 ), 130.82(C 16 ), 130.22(C

  A7B4:1 H NMR (500 MHz, CD3CN): δ =8.16 (s, 1H, H 5 ), 7.66-7.54 (m, 2H, H 3,3' ), 7.48-7.41 (m, 2H, H 8,8' ), 7.41-7.21 (m, 2H, H 9,9' ), 7.21-6.88 (m, 1H, H 10 ), 5.17 (s, 2H, H 6 );[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR (125 MHz, CD3CN): δ 165.26(C 4 ), 163.29 (C 1 ), 148.62(C 5 ), 138.65(C 7 ), 129.67(C 3 ), 129.61(C 3' ) , 129.11(C 9,9' ), 129.06(C 8,8' ), 128.61(C 10 ), 116.53 (C 2 ), 116.35(C 2' ), 76.62(C 6 ).;

ESI-MS: calculated for [C14H12FNO+H] + 230.0976, found, 230.0971; Elemental analysis calculated (%) for C14H12FNO:

C, 73.35; H, 5.28; F, 8.29; N, 6.11; O, 6.98; found : C, 72.99; H, 5.30; N, 6.25.

  ), 7. 2H, H 3,3' ), 7.82 (s, 1H, H 5 ), J = 10.0 Hz, 1H, H 8 ), 7.70 (t, 1H, H 9 ), 6.89 (t, 1H, H 10 ), 3.67 (s, 3H, H 6 );[START_REF] Hasenknopf | Self-Assembly of Tetra-and Hexanuclear Circular Helicates[END_REF] C NMR (126 MHz, CD3CN): δ 157.98(C 7 ), 147.79(C 11 ), 147.70 (C 1 ), 143.59(C 4 ), 138.55(C 9 ), 132.74(C 5 ), 127.20(C 3,3' ), 124.73(C 2,2' ), 117.13(C 10 ), 110.48 (C

[START_REF] Cram | International Edition in English[END_REF]

),

29

.93

(C 6

). ESI-MS: calculated for [C14H12N2O3+H] + 257.1039, found: 257.1026; Elemental analysis calculated (%) for C14H12N2O3

: C, 60.93; H, 4.72; N, 21.86; O, 12.49; found: C, 60.75; H, 4.79; N, 21.75.

Table III16 .

 III16 Time-dependent of the evolution of DCL distributions generated from equal amounts of A1 + A6 + B3 + B4.

	Entry	t [h]

  The reaction was performed in CD3CN,30 mM each, r.t. [b] Reaction times indicate the time at which distribution data were collected. [c] Error in 1 H-NMR signal integration: 5%.

	1 [a]	0.5	10%	20%	40%	1%	29%	<1%
	2 [a]	10	2%	8%	26%	25%	27%	14%
	3 [a]	46	0%	2%	19%	32%	25%	21%
	[a]

M -1 s -1 (entry 8 in Table

4), a value which exceeds that of the formation of A3B1 in the absence

Acknowledgements

vii

ACKNOWLEDGEMENTS

Firstly, I would like to express my sincere thanks to Prof. Jean-Marie Lehn for giving me this fantastic opportunity to do my Ph.D in his research group. I got enormous inspiration and motivation by his enthusiasm on science, excellent instructions, and amazing personality. I appreciate for his patient guidance, kind support and immense knowledge. It was such great Acknowledgements viii There are many friends who I very much appreciate, Xiaoqiao, Zhuo, Xue, Yali, Jia, Gaigai, Yongmei, Thanvy, Xingmao, Rui, Jiayun, Yanyu and Xiaomin for their kindness.

Last but not least, I would like to thank my parents, my sisters and brother for supporting me spiritually throughout my Ph.D life in France. The most special thank I would give to my husband Shaofei Zhang, who is always supporting me and accompanying me.

Finally, I would like to acknowledge the "China Scholarship Council" and Prof. Jean-Marie Lehn, for their financial support on my Ph.D study. Without these, I would not have been here to pursue my research.

iii. High resolution electrospray ionization mass spectroscopy

High resolution electrospray ionization mass spectroscopy (HR-ESI-MS) analysis were performed on a ThermoFisher Exactive Plus EMR Orbitrap mass spectrometer.

iv. Elemental Analysis

Elemental analysis was performed on a ThermoFischer Scientific Flash 200 with absolute precision of 0.3% at the service de Microanalyse, University of Strasbourg. The data were given by the percentage of the elements C, H and N.

v. X-ray crystallography

X-ray crystallography was performed at the service de radiocristallographie, university of Strasbourg.

vi. pH Measurement

All pH and pD were measured directly after calibration of pH meter in aqueous pH 2, pH 4.1, pH 7, and pH 10 buffer (Fluka) on a SEVENCOMPACT TM pH/Ion meter S220 using a

Hamilton Spintrode mini-probe.

2) Kinetics of A1 + B1 in presence of 0.05 equiv. of Zn(OTf)2

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