Living systems can respond to their environment through signal transduction cascades. In these cascades, original stimuli are amplified and translated into reaction or assembly events. In an effort to instill synthetic materials with biomimetic responsivity, we report an aggregation process forming a supramolecular network held together by host-guest interactions that is responsive to nucleophilic chemical signals through a chemical reaction-assembly cascade. In particular, we developed a signal-induced switch between cucurbit[8]uril binary and ternary complexes with cationic bipyridine derivatives where the charge on the bipyridine can be changed through an allylic substitution reaction with the nucleophilic signal. When applied to a multitopic bipyridine guest, the reaction with the nucleophile signals leads to supramolecular network formation where the aggregation rates and final structure depend on the nucleophilicity of the signal. This work opens the door to new opportunities for signal-responsive synthetic materials and interactions with biological systems.

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In the quest for stimuli-responsive materials with specific, controllable functions, coacervate hydrogels have become a promising candidate, featuring sensitive responsiveness to environmental signals enabling control over sol-gel transitions. However, conventional coacervation-based materials are regulated by relatively non-specific signals, such as temperature, pH or salt concentration, which limits their possible applications. In this work, we constructed a coacervate hydrogel with a Michael addition-based chemical reaction network (CRN) as a platform, where the state of coacervate materials can be easily tuned by specific chemical signals. We designed a pyridine-based ABA triblock copolymer, whose quaternization can be regulated by an allyl acetate electrophile and an amine nucleophile, leading to gel construction and collapse in the presence of polyanions. Our coacervate gels showed not only highly tunable stiffness and gelation times, but excellent self-healing ability and injectability with different sized needles, and accelerated degradation resulting from chemical signal-induced coacervation disruption. This work is expected to be a first step in the realization of a new class of signal-responsive injectable materials.

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The field of supramolecular chemistry is rapidly progressing, transitioning from the creation of thermodynamically stable systems found in local or global minima on the free energy landscape to the development of out-of-equilibrium systems that rely on chemical reactions to establish and maintain their structures. Over the past decade, numerous artificial out-of-equilibrium systems have been devised in various domains of supramolecular chemistry, many of which have been extensively reviewed. However, one area that has received limited attention thus far is the use of out-of-equilibrium processes to regulate host–guest interactions. This minireview aims to address this gap by exploring the construction of out-of-equilibrium systems based on host–guest complexation, which likely employs similar strategies to those employed in analogous noncovalent interactions. The review begins with a summary of these shared strategies. Subsequently, it discusses representative publications that exemplify these strategies and classifies them based on which component is being modulated–host, guest, or competitive molecules. Through this examination, our objective is to shed light on the design of out-of-equilibrium systems relying on host–guest interactions and provide valuable insights into the preparation strategies for various transient materials.

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Signal transduction mechanisms are key to living systems. Cells respond to signals by changing catalytic activity of enzymes. This signal responsive catalysis is crucial in the regulation of (bio)chemical reaction networks (CRNs). Inspired by these networks, we report an artificial signal responsive system that shows signal-induced temporary catalyst activation. We use an unstable signal to temporarily activate an out of equilibrium CRN, generating transient host-guest complexes to control catalytic activity. Esters with favorable binding toward the cucurbit[7]uril (CB[7]) supramolecular host are used as temporary signals to form a transient complex with CB[7], replacing a CB[7]-bound guest. The esters are hydrolytically unstable, generating acids and alcohols, which do not bind to CB[7], leading to guest reuptake. We demonstrate the feasibility of the concept using signal-controlled temporary dye release and reuptake. The same signal controlled system was then used to tune the reaction rate of aniline catalyzed hydrazone formation. Varying the ester structure and concentration gave access to different catalyst liberation times and free catalyst concentration, regulating the overall reaction rate. With temporary signal controlled transient complex formation we can tune the kinetics of a second chemical reaction, in which the signal does not participate. This system shows promise for building more complex nonbiological networks, to ultimately arrive at signal transduction in organic materials.

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Nature has proven to be a great source of inspiration for scientific research and technological innovation in various areas: food, medicine, architecture, chemistry, materials, algorithms, and many other fields. At the basis of sophisticated functions associated with life in nature are all kinds of chemical reactions which are mainly regulated by enzymes through molecular recognition of the substrates. Meanwhile, chemical signals are able to tune the catalytic activities of enzymes through noncovalent bonding or structural modification. Concomitantly, the formation of transient structures that are used temporarily, for instance the mitotic spindle, requires the conversion of energy, mainly in the form of high-energy chemical fuels. All of these phenomena combined endow living systems with high responsivity to various stimuli. Inspired by nature, regulating artificial catalysts in chemical reactions by noncovalent bonding, and controlling formation/deformation of supramolecular materials by chemical reactions are attracting researchers’ attention. This thesis integrates chemical reaction networks with host-guest complexation, aiming to bring about some of these advanced properties. @en

Dynamic regulation of chemical reactivity is important in many complex chemical reaction networks, such as cascade reactions and signal transduction processes. Signal responsive catalysts could play a crucial role in regulating these reaction pathways. Recently, supramolecular encapsulation was reported to regulate the activities of artificial catalysts. We present a host-guest chemistry strategy to modulate the activity of commercially available synthetic organocatalysts. The molecular container cucurbit[7]uril was successfully applied to change the activity of four different organocatalysts and one initiator, enabling up- or down-regulation of the reaction rates of four different classes of chemical reactions. In most cases CB[7] encapsulation results in catalyst inhibition, however in one case catalyst activation by binding to CB[7] was observed. The mechanism behind this unexpected behavior was explored by NMR binding studies and pKa measurements. The catalytic activity can be instantaneously switched during operation, by addition of either supramolecular host or competitive binding molecules, and the reaction rate can be predicted with a kinetic model. Overall, this signal responsive system proves a promising tool to control catalytic activity.

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Fuel-driven chemical reaction networks provide an opportunity to develop chemical systems that operate out-ofequilibrium. There remains a need to design and develop new fueldriven chemical reaction networks capable of repeated operation using simple and benign chemistry. Here, we propose a new chemical reaction network for fuel-driven transient formation of covalent bonds,
based on redox-controlled conjugate addition and elimination chemistry. By investigating the separate reactions making up the cycle, we find that the bond formation, breaking and regeneration processes can be realized. At present, substantial side reactivity prevents achieving repeated operation of a full cycle in a single system. If such obstacles would be overcome, this chemical reaction
network could be a valuable addition to the toolbox for out-ofequilibrium
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