Higher Order Constitutional Dynamic Networks: [2×3] and [3×3] Networks Displaying Multiple, Synergistic and Competitive Hierarchical Adaptation

The present study investigates the constitutional dynamic networks (CDNs) underlying dynamic covalent libraries (DCLs) that extend beyond the [2×2] case toward higher orders, namely [2×3] and [3×3] CDNs involving respectively six and nine constituents generated from the recombination of five and six components linked through reversible chemical reactions. It explores the behavior of such systems under the action of one or two effectors. More specifically and for the sake of proof of principle, it makes use of DCLs involving dynamic organic ligands and analyzes their single and double adaptive response under the action of one and two metal cation effectors. Thus, interconversions within [2×3] DCLs of six constituents (hydrazone, acylhydrazone, and imine ligands) give access to the generation of [2×3] CDNs of 3D trigonal prismatic type consisting of three [2×2] sub-networks and presenting specific responses to the application of Cu⁺ and Zn²⁺ metal cation effectors, in particular double agonistic amplification. More complex [3×3] CDNs based on nine ligand constituents of imine, hydrazone, and acylhydrazone types were also designed and subjected to the application of one or two effectors, e.g., Cu⁺ and Fe²⁺ metal cations, revealing novel types of adaptive behavior: (i) agonistic amplification between a single constituent and a full [2×2] sub-network, and (ii) agonistic amplification along a single diagonal connecting three constituents. Of special interest is also the dependence of the response of the system to hierarchical sequence of effector application, whereby initial interaction with Cu⁺ ions results in the destruction of the network, whereas the sequence Fe²⁺ followed by Cu⁺ yields a clean three-constituent DCL. Finally and strikingly, the present results also demonstrate that the increase in complexity of the system by introduction of an additional entity leads to a simpler output through dynamic competition between components

The Photodynamic Covalent Bond: Sensitized Alkoxyamines as a Tool To Shift Reaction Networks Out-of-Equilibrium Using Light Energy

We implement sensitized alkoxyamines as “photodynamic covalent bonds”bonds that, while being stable in the dark at ambient temperatures, upon photoexcitation efficiently dissociate and recombine to the bound state in a fast thermal reaction. This type of bond allows for the photochemically induced exchange of molecular building blocks and resulting constitutional variation within dynamic reaction networks. To this end, alkoxyamines are coupled to a xanthone unit as triplet sensitizer enabling their reversible photodissociation into two radical species. By studying the photochemical properties of three generations of sensitized alkoxyamines it became clear that the nature and efficiency of triplet energy transfer from the sensitizer to the alkoxyamine bond as well as the reversibility of photodissociation crucially depends on the structure of the nitroxide terminus. By employing the thus designed photodynamic covalent bonding motif, we demonstrate how to use light energy to shift a dynamic covalent reaction network away from its thermodynamic minimum into a photostationary state. The network could be repeatedly switched between its minimum and kinetically trapped out-of-equilibrium state by thermal scrambling and selective photoactivation of sensitized alkoxyamines, respectively

Light-Driven Molecular Motors: Imines as Four-Step or Two-Step Unidirectional Rotors

Chiral <i>N</i>-alkyl imines undergo unidirectional rotation induced by light and heat, thus providing a new class of molecular motors. Depending on the conformational flexibility of the stator part (the carbonyl residue) and the nitrogen inversion barrier of the rotor part (the amine residue) in the molecule, the operation mode of the motor can be controlled as either a four- or a two-step cycling motion of the rotor part

Adaptation of Dynamic Covalent Systems of Imine Constituents to Medium Change by Component Redistribution under Reversible Phase Separation

A dynamic covalent library of interconverting imine constituents, dissolved in an acetonitrile/water mixture, undergoes constitutional reorganization upon phase separation induced by a physical stimulus (heat) or a chemical effector (inorganic salt, carbohydrate, organic solvent). The process has been made reversible, regenerating the initial library upon phase reunification. It represents the behavior of a dynamic covalent library upon reversible phase separation and its adaptation to a phase change, with up-regulation in each phase of the fittest constituents by component selection. Finally, the system exemplifies the splitting of a 2D (square) constitutional dynamic network into a 3D (cube) one

Merging Constitutional and Motional Covalent Dynamics in Reversible Imine Formation and Exchange Processes

The formation and exchange processes of imines of salicylaldehyde, pyridine-2-carboxaldehyde, and benzaldehyde have been studied, showing that the former has features of particular interest for dynamic covalent chemistry, displaying high efficiency and fast rates. The monoimines formed with aliphatic α,ω-diamines display an internal exchange process of self-transimination type, inducing a local motion of either “stepping-in-place” or “single-step” type by bond interchange, whose rate decreases rapidly with the distance of the terminal amino groups. Control of the speed of the process over a wide range may be achieved by substituents, solvent composition, and temperature. These monoimines also undergo intermolecular exchange, thus merging motional and constitutional covalent behavior within the same molecule. With polyamines, the monoimines formed execute internal motions that have been characterized by extensive one-dimensional, two-dimensional, and EXSY proton NMR studies. In particular, with linear polyamines, nondirectional displacement occurs by shifting of the aldehyde residue along the polyamine chain serving as molecular track. Imines thus behave as simple prototypes of systems displaying relative motions of molecular moieties, a subject of high current interest in the investigation of synthetic and biological molecular motors. The motional processes described are of dynamic covalent nature and take place without change in molecular constitution. They thus represent a category of dynamic covalent motions, resulting from reversible covalent bond formation and dissociation. They extend dynamic covalent chemistry into the area of molecular motions. A major further step will be to achieve control of directionality. The results reported here for imines open wide perspectives, together with other chemical groups, for the implementation of such features in multifunctional molecules toward the design of molecular devices presenting a complex combination of motional and constitutional dynamic behaviors

Nonlinear Kinetic Behavior in Constitutional Dynamic Reaction Networks

Creating synthetic chemical systems which emulate the complexity observed in cells relies on exploiting chemical networks exhibiting nonlinear kinetic behavior. While control over reaction complexity using synthetic gene regulatory networks and DNA nanotechnology has developed greatly, little control exists over small molecule reaction networks. Toward this goal, we demonstrate a general framework for inducing nonlinear kinetic behavior in dynamic chemical networks based on molecules containing reversible chemical bonds. Specifically, this strategy relies on constituent species with differing thermodynamic stabilities that readily exchange components at rates that are faster than their formation rates. Such nonlinear networks (NLN) readily lead to sigmoidal kinetic profiles as a function of the relative thermodynamic stabilities of the constituent species. Furthermore, this behavior could be readily extended to more complex mixtures while maintaining nonlinearity. The generality of this method opens the possibility to generate nonlinear networks using a broad range of small molecule structures

Dynamic Covalent Metathesis in the CC/CN Exchange between Knoevenagel Compounds and Imines

Fast and reversible dynamic covalent CC/CN exchange takes place without catalyst in nonpolar solvents between barbiturate-derived Knoevenagel (Kn) compounds and imines. A detailed study of the reaction indicates that it proceeds by an associative organo-metathesis mechanism involving the formation of a four-membered ring azetidine intermediate by addition of the imine CN group to the CC bond of the Kn compound. This intermediate could be generated cleanly and stabilized at low temperature by condensation of the <i>o,p</i>-dinitrophenyl Kn derivative with the cyclic imine 1-azacyclohexene. It was characterized by extensive NMR and mass spectrometric studies. The process described represents a genuine dynamic covalent organo-metathesis through a four-membered ring adduct as intermediate. It paves the way for the exploration of a wide set of dynamic systems involving (strongly) polarized CC bonds and various imines, extending also into covalent dynamic polymers and polymolecular assemblies

Dynamic Covalent Metathesis in the CC/CN Exchange between Knoevenagel Compounds and Imines

Fast and reversible dynamic covalent CC/CN exchange takes place without catalyst in nonpolar solvents between barbiturate-derived Knoevenagel (Kn) compounds and imines. A detailed study of the reaction indicates that it proceeds by an associative organo-metathesis mechanism involving the formation of a four-membered ring azetidine intermediate by addition of the imine CN group to the CC bond of the Kn compound. This intermediate could be generated cleanly and stabilized at low temperature by condensation of the <i>o,p</i>-dinitrophenyl Kn derivative with the cyclic imine 1-azacyclohexene. It was characterized by extensive NMR and mass spectrometric studies. The process described represents a genuine dynamic covalent organo-metathesis through a four-membered ring adduct as intermediate. It paves the way for the exploration of a wide set of dynamic systems involving (strongly) polarized CC bonds and various imines, extending also into covalent dynamic polymers and polymolecular assemblies

Training a Constitutional Dynamic Network for Effector Recognition: Storage, Recall, and Erasing of Information

Constitutional dynamic libraries (CDLs) of hydrazones, acylhydrazones, and imines undergo reorganization and adaptation in response to chemical effectors (herein metal cations) via component exchange and selection. Such CDLs can be subjected to training by exposition to given effectors and keep memory of the information stored by interaction with a specific metal ion. The long-term storage of the acquired information into the set of constituents of the system allows for fast recognition on subsequent contacts with the same effector(s). Dynamic networks of constituents were designed to adapt orthogonally to different metal cations by up- and down-regulation of specific constituents in the final distribution. The memory may be erased by component exchange between the constituents so as to regenerate the initial (statistical) distribution. The libraries described represent constitutional dynamic systems capable of acting as information storage molecular devices, in which the presence of components linked by reversible covalent bonds in slow exchange and bearing adequate coordination sites allows for the adaptation to different metal ions by constitutional variation. The system thus performs information storage, recall, and erase processes

Adaptation in Constitutional Dynamic Libraries and Networks, Switching between Orthogonal Metalloselection and Photoselection Processes

Constitutional dynamic libraries of hydrazones ^<b>a</b><b>A</b>^<b>b</b><b>B</b> and acylhydrazones ^<b>a</b><b>A</b>^<b>c</b><b>C</b> undergo reorganization and adaptation in response to a chemical effector (metal cations) or a physical stimulus (light). The set of hydrazones [^<b>1</b><b>A</b>^<b>1</b><b>B</b>, ^<b>1</b><b>A</b>^<b>2</b><b>B</b>, ^<b>2</b><b>A</b>^<b>1</b><b>B</b>, ^<b>2</b><b>A</b>^<b>2</b><b>B</b>] undergoes metalloselection on addition of zinc cations which drive the amplification of Zn­(^<b>1</b><b>A</b>^<b>2</b><b>B</b>)₂ by selection of the fittest component ^<b>1</b><b>A</b>^<b>2</b><b>B</b>. The set of acylhydrazones [<i>E</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b>, ^<b>1</b><b>A</b>^<b>2</b><b>C</b>, ^<b>2</b><b>A</b>^<b>1</b><b>C</b>, ^<b>2</b><b>A</b>^<b>2</b><b>C</b>] undergoes photoselection by irradiation of the system, which causes photoisomerization of <i>E</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b> into <i>Z</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b> with amplification of the latter. The set of acyl hydrazones [<i>E</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b>, ^<b>1</b><b>A</b>^<b>3</b><b>C</b>, ^<b>2</b><b>A</b>^<b>1</b><b>C</b>, ^<b>2</b><b>A</b>^<b>3</b><b>C</b>] undergoes a <i>dual adaptation</i> via component exchange and selection in response to two orthogonal external agents: a chemical effector, metal cations, and a physical stimulus, light irradiation. <i>Metalloselection</i> takes place on addition of zinc cations which drive the amplification of Zn­(^<b>1</b><b>A</b>^<b>3</b><b>C</b>)₂ by selection of the fittest constituent ^<b>1</b><b>A</b>^<b>3</b><b>C</b>. <i>Photoselection</i> is obtained on irradiation of the acylhydrazones that leads to photoisomerization from <i>E</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b> to <i>Z</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b> configuration with amplification of the latter. These changes may be represented by square constitutional dynamic networks that display up-regulation of the pairs of agonists (^<b>1</b><b>A</b>^<b>2</b><b>B</b>, ^<b>2</b><b>A</b>^<b>1</b><b>B</b>), (<i>Z</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b>, ^<b>2</b><b>A</b>^<b>2</b><b>C</b>), (^<b>1</b><b>A</b>^<b>3</b><b>C</b>, ^<b>2</b><b>A</b>^<b>1</b><b>C</b>), (<i>Z</i>-^<b>1</b><b>A</b>^<b>1</b><b>C</b>, ^<b>2</b><b>A</b>^<b>3</b><b>C</b>) and the simultaneous down-regulation of the pairs of antagonists (^<b>1</b><b>A</b>^<b>1</b><b>B</b>, ^<b>2</b><b>A</b>^<b>2</b><b>B</b>), (^<b>1</b><b>A</b>^<b>2</b><b>C</b>, ^<b>2</b><b>A</b>^<b>1</b><b>C</b>), (<i>E</i>-^<b>1</b><b>A</b>^<b>1</b><b>C,</b> ^<b>2</b><b>A</b>^<b>3</b><b>C</b>), (^<b>1</b><b>A</b>^<b>3</b><b>C</b>, ^<b>2</b><b>A</b>^<b>1</b><b>C</b>). The orthogonal dual adaptation undergone by the set of acylhydrazones amounts to a network switching process