Dynamic Covalent Reactions Research Articles

Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions

AbstractMutualisms are interactions that benefit all species involved. It has been widely investigated in neighbouring subjects, such as biology, ecology, sociology, and economics. However, such a reciprocal relationship in synthetic chemical systems has rarely been studied. Here, we demonstrate a mutualistic synthesis where byproducts from two orthogonal chemical reactions aid each other′s production. Disulfide exchange and hydrazone exchange were chosen to generate two dynamic combinatorial libraries. A minor tetrameric macrocycle from the active disulfide library was quantitatively amplified in the presence of the hydrazone library. This incorporation also turned on the previously inert hydrazone reaction, producing a linear species that formed a “handcuffs” catenane with the disulfide tetramer. These findings not only lend robust support to the hypothesis of “RNA‐peptide coevolution” for the origin of life but also broaden the scope of synthetic chemistry, highlighting the untapped potential of minor products from different reactions. Additionally, the co‐self‐assembly of these mutualistic entities to form supramolecular structures opens new avenues for future development of composite nanosystems with synergistic properties.

Cover Picture: Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions (Angew. Chem. Int. Ed. 44/2024)

Cover Picture: Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions (Angew. Chem. Int. Ed. 44/2024)

Titelbild: Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions (Angew. Chem. 44/2024)

Titelbild: Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions (Angew. Chem. 44/2024)

Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions.

Mutualisms are interactions that benefit all species involved. It has been widely investigated in neighbouring subjects, such as biology, ecology, sociology, and economics. However, such a reciprocal relationship in synthetic chemical systems has rarely been studied. Here, we demonstrate a mutualistic synthesis where byproducts from two orthogonal chemical reactions aid each other's production. Disulfide exchange and hydrazone exchange were chosen to generate two dynamic combinatorial libraries. A minor tetrameric macrocycle from the active disulfide library was quantitatively amplified in the presence of the hydrazone library. This incorporation also turned on the previously inert hydrazone reaction, producing a linear species that formed a "handcuffs" catenane with the disulfide tetramer. These findings not only lend robust support to the hypothesis of "RNA-peptide coevolution" for the origin of life but also broaden the scope of synthetic chemistry, highlighting the untapped potential of minor products from different reactions. Additionally, the co-self-assembly of these mutualistic entities to form supramolecular structures opens new avenues for future development of composite nanosystems with synergistic properties.

Hyaluronic Acid/Chondroitin Sulfate-Based Dynamic Thiol-Aldehyde Addition Hydrogel: An Injectable, Self-Healing, On-Demand Dissolution Wound Dressing.

Frequent removal and reapplication of wound dressings can cause mechanical disruption to the healing process and significant physical discomfort for patients. In response to this challenge, a dynamic covalent hydrogel has been developed to advance wound care strategies. This system comprises aldehyde functionalized chondroitin sulfate (CS-CHO) and thiolated hyaluronic acid (HA-SH), with the distinct ability to form in situ via thiol-aldehyde addition and dissolve on-demand via the thiol-hemithioacetal exchange reaction. Although rarely reported, the dynamic covalent reaction of thiol-aldehyde addition holds great promise for the preparation of dynamic hydrogels due to its rapid reaction kinetics and easy reversible dissociation. The thiol-aldehyde addition chemistry provides the hydrogel system with highly desirable characteristics of rapid gelation (within seconds), self-healing, and on-demand dissolution (within 30 min). The mechanical and dissolution properties of the hydrogel can be easily tuned by utilizing CS-CHO materials of different aldehyde functional group contents. The chemical structure, rheology, self-healing, swelling profile, degradation rate, and cell biocompatibility of the hydrogels are characterized. The hydrogel possesses excellent biocompatibility and proves to be significant in promoting cell proliferation in vitro when compared to a commercial hydrogel (HyStem® Cell Culture Scaffold Kit). This study introduces the simple fabrication of a new dynamic hydrogel system that can serve as an ideal platform for biomedical applications, particularly in wound care treatments as an on-demand dissolvable wound dressing.

Porous Crystalline Organic Cages Made by Design

AbstractShape‐persistent organic cages are an intriguing class of molecular porous materials. Through hierarchical molecular design, size and shape of the intrinsic molecular voids are controlled by dynamic covalent chemistry, while pore structure and topology are governed by noncovalent alignment in the solid state. However, the predictable and reliable crystallization of organic cages is still challenging since long‐range superstructures are solely based on weak and rather unidirectional supramolecular interactions. In this tutorial review, we provide a general classification of porous solid‐state materials and discuss specific design principles regarding the dynamic covalent reactions, the small‐molecule building blocks and solid‐state engineering. Furthermore, we introduce the most important analytical techniques for porous materials with a special focus on organic cages.

Switching between Nonisoenergetic Dynamic Covalent Reactions Using Host-Guest Chemistry.

CO2 reacts with simple amines in the presence of water to generate dynamic combinatorial libraries of majority (i.e., ammonium carbamates) and minority (i.e., ammonium carbonates) nonisoenergetic covalent adducts. Over the past two decades, our laboratory has reported on a new class of cavitands, namely, dyn[n]arenes, from which a polyanionic macrocycle is a highly efficient receptor for linear polyammoniums that forms [2]pseudorotaxanes in water at neutral pH. Herein, we demonstrate that the formation of [2]pseudorotaxanes shifts the equilibrium of CO2 capture by polyamines in water toward the quasi-exclusive formation of carbonate adducts, providing the first example of a switch between two competitive and reversible covalent processes triggered by host-guest interactions. In addition, this supramolecular approach to CO2 capture exhibits enhanced capture efficiency by increasing the state of protonation of complexed vs uncomplexed polyamines. Altogether, we report here that a templating approach can divert the outcome of two reversible covalent chemistries involving nucleophilic additions and acid-base reactions, challenging therefore the common knowledge that noncovalent and covalent bonds operate in separate energy frames.

Dynamic Covalent Synthesis Applied to Optoelectronic and Energy Materials: Design, Applications and Limitations

AbstractDynamic Covalent Chemistry, consisting in the use of dynamic covalent bonds (DCBs) to create complex objects by working at the thermodynamic equilibrium, has undeniable advantages for the preparation of conjugated systems with tailored optoelectronic properties for organic electronics. Chemists can combine simple building blocks with simple functional groups of appropriate geometry, structure and stoichiometry to build multidimensional conjugated architectures. Dynamic covalent reactions are often precious metal‐free, generate little to no side products and are very efficient. DCBs however afford sensitive materials, and consequently a balance needs to be found between the ease of synthesis, the stability and the performances. The dynamicity of the target materials hence can considerably reduce their applicability in organic electronics where strongly stable materials are needed, but opens the door to stimuli‐responsive behaviour and recyclability. A way to overcome dynamicity issues is to lock DCBs, but often at the cost of decreased conjugation. In this review, we will highlight how DCBs are employed to prepare functional optoelectronically active materials, such as discrete molecules, polymers or covalent organic frameworks, applied in fields ranging from organic light‐emitting diodes and solar cells to organic batteries and transistors. We will also discuss their limitations, benefits and the current challenges to overcome.

Effects of additional ring-fusion site on dual reactivity based dynamic covalent chemistry

Tautomers are widespread in organic chemistry, and their unique reactivity allows diverse transformations. In this work, the incorporation of nearby amide ring-fusion site offered a versatile platform for controlling dual reactivity based dynamic covalent chemistry (DCC) of aldehyde ring-chain tautomers. A suite of 2-formylbenzosulfonamide derived tautomers were prepared, and the intramolecular ring-chain equilibrium and intermolecular dynamic covalent reactions along the underlying mechanistic foundation were investigated. By regulating the substituent electronic effect and solvent effect, ring-chain tautomerization equilibrium was readily regulated in solution. The adjacent amide NH participates in intramolecular hydrogen bonding, as revealed by crystal analysis. Furthermore, the addition of acid and the change of solvent allowed turning on/off the intramolecular cyclization from the amide group to create fused ring scaffolds. Finally, the reversible covalent reactions with amine nucleophile reagents maintained the intermolecular reactivity successfully. The molecular and pathway diversity reported herein sets the scene for future design and applications.

Multiple control of azoquinoline based molecular photoswitches.

Multi-addressable molecular switches with high sophistication are creating intensive interest, but are challenging to control. Herein, we incorporated ring-chain dynamic covalent sites into azoquinoline scaffolds for the construction of multi-responsive and multi-state switching systems. The manipulation of ring-chain equilibrium by acid/base and dynamic covalent reactions with primary/secondary amines allowed the regulation of E/Z photoisomerization. Moreover, the carboxyl and quinoline motifs provided recognition handles for the chelation of metal ions and turning off photoswitching, with otherwise inaccessible Z-isomer complexes obtained via the change of stimulation sequence. Particularly, the distinct metal binding behaviors of primary amine and secondary amine products offered a facile way for modulating E/Z switching and dynamic covalent reactivity. As a result, multiple control of azoarene photoswitches was accomplished, including light, pH, metal ions, and amine nucleophiles, with interplay between diverse stimuli further enabling addressable multi-state switching within reaction networks. The underlying structural and mechanistic insights were elucidated, paving the way for the creation of complex switching systems, molecular assemblies, and intelligent materials.

Dynamic covalent chemistry for self-erasable fluorescent organogel

Information encryption has always played an important role in life. Herein, we have developed a self-erasable fluorescent material based on the non-equilibrium dynamic cross-linking reaction between the naphthalene and triazolinedione groups, which undergo cycloaddition under 525 nm light and spontaneous dissociation with the light off. The dynamic covalent reaction between these groups could effectively control the emission behavior of the material, allowing the visual track of chemically triggered covalent bonding processes in gelation and de-gelation of soft organogels. In addition, a light-responsive self-erasable fluorescent anti-counterfeiting system with information storage, encryption, self-erasing, and rewritability has been prepared. This material has exhibited self-erasable ability and improved the security for information encryption. Moreover, a “time-lock” information encryption system has been developed based on the irradiation time-dependent fluorescent property of this material. The development of this information encryption system not only simplifies the operation of encrypting and decrypting information but also improves their security level.

Programmable liquid crystal elastomers with dynamic covalent siloxane bonds based on a dual self-catalytic strategy

The exchange reaction of preparing the siloxane-based liquid crystal elastomers (Si-LCEs) always require the acid or base catalysts, which will increase the complexity of the operation and reduces the stability of the Si-LCE materials. In this paper, a novel and simple dual self-catalytic strategy for producing Si-LCEs with dynamic covalent siloxane bonds was proposed. A readily available compound-1,3-bis (aminopropyl) tetramethyldisiloxane (BATS) acts as chain extender and crosslinker for elastomers and provides dynamic covalent bonds (DCBs) as well. More importantly, amino groups of BATS play the role of dual self-catalyst, not only accelerating the thiol Michael addition reaction and aza Michael addition reaction simultaneously during producing Si-LCEs, but also promoting dynamic covalent siloxane bonds exchange reaction at an elevated temperature after the formation of the cross-linked network. With this ingenious design, the obtained fully cured polydomain Si-LCEs possess excellent self-healing and processing abilities enabled by DCBs and outstanding mechanical properties facilitated by hydrogen bond, which can be easily aligned, programmed and recycled. By exploiting these dynamic features, a series of multi-functional soft actuators were realized by simple welding, showing a local fast response and precise control by light and heat. Furthermore, soft robots fabricated with a bilayer structure of Si-LCEs can perform crawling and coiling actuation controlled by near-infrared (NIR) light facilely. These results manifest that the self-catalytic dynamic covalent siloxane bonds strategy is a facile and effective approach for preparing Si-LCEs and provides a new solution for the exploitation of multi-functional liquid crystal elastomers with fast response to various stimulus.

A tetraaldehyde-derived porous organic cage and covalent organic frameworks: Syntheses, structures, and iodine vapor capture

Dynamic covalent imine reactions between 2′,3′-dimethoxy-[1,1′:4′,1″-terphenyl]-3,3″,5,5″-tetracarbaldehyde (DMTT) and cyclohexanediamine, p-phenylenediamine, and benzidine, respectively, generate a porous organic cage (DMPOC) and two covalent organic frameworks (COFs), USTB-29, and USTB-30. DMPOC shows a [3 + 6] topological cage-like structure according to single crystal X-ray diffraction result. In contrast, both microcrystalline USTB-29 and USTB-30 exhibit two-dimensional monoporous structures in an eclipsed AA stacking style based on powder X-ray diffraction and theoretical simulations. In addition, DMPOC is capable of efficiently absorbing the iodine vapor with an outstanding uptake of 5.10 g/g, much higher than that of USTB-29 (3.07 g/g) and USTB-30 (3.16 g/g). Cage to COFs transformations have been realized from DMPOC to USTB-29 and USTB-30 via the imine bond exchange with slightly increased iodine vapor uptake. Mechanism investigations uncover that both nitrogen and oxygen atoms of POC and COFs contribute to iodine vapor capture due to the formation of charge transfer matter, and loose interaction introducing adaptive expanding voids of DMPOC is suggested to capture more iodine vapor than that of COFs with strong π-π interactions.

Kinetic control over co-self-assembly using an in situ dynamic covalent reaction resulting in a synergistic chemo-photodynamic therapy

Kinetic control over co-self-assembly using an in situ dynamic covalent reaction resulting in a synergistic chemo-photodynamic therapy

Stimuli-Responsive Codelivery System Self-Assembled from in Situ Dynamic Covalent Reaction of Macrocyclic Disulfides for Cancer Magnetic Resonance Imaging and Chemotherapy.

Supramolecular self-assembly has gained increasing attention to construct multicomponent drug delivery systems for cancer diagnosis and therapy. Despite that these self-assembled nanosystems present surprising properties beyond that of each subcomponent, the spontaneous nature of co-self-assembly causes significant difficulties in control of the synthesis process and consequently leads to unsatisfactory influences in downstream applications. Hence, we utlized an in situ dynamic covalent reaction based on thiol-disulfide exchange to slowly produce disulfide macrocycles, which subsequently triggered the co-self-assembly of an anticancer drug (doxorubicin, DOX) and a magnetic resonance imaging (MRI) contrast agent of ultrasmall iron oxide nanoparticles (IO NPs). It showed concentration regulation of macrocyclic disulfides, DOX, and IO NPs by a dynamic covalent self-assembly (DCS) strategy, resulting in a stable codelivery nanosystem with high drug loading efficiency of 37.36%. More importantly, disulfide macrocycles in the codelivery system could be reduced and broken by glutathione (GSH) in tumor cells, thus leading to disassembly of nanostructures and intellgent release of drugs. These stimuli-responsive performances have been investigated via morphologies and molecular structures, revealing greatly enhanced dual-modal MRI abilities and smart drug release under the trigger of GSH. Moreover, the codelivery system conjugated with a targeting molecule of cyclic Arg-Gly-Asp (cRGD) exhibited significant biocompatibility, MR imaging, and chemotherapeutic anticancer effect in vitro and in vivo. These results indicated that in situ dynamic covalent chemistry enhanced the control over co-self-assembly and paved the way to develop more potential drug delivery systems.

A phosphonate‐derived epoxy vitrimer with intrinsic flame retardancy and catalyst‐free reprocessability

AbstractPhosphonate, as an effective flame‐retardant group, has a dynamic phosphonate exchange behavior similar to the transesterification of carboxylate; and introducing it into the network of epoxy resin (EP) is beneficial for solving the fire risk and waste disposal problems of EP in the meantime. Herein, a reprocessable and flame‐retardant epoxy vitrimer (EV) with dual dynamic covalent reactions of phosphonate and carboxylate transesterifications is constructed by introducing a phosphonate‐containing diol named GHPP into an epoxy‐anhydride curing system. The presence of the phosphonate makes the EV intrinsically flame‐retardant; meanwhile, both of the dynamic phosphonate and carboxylate transesterifications are accelerated by the abundant primary hydroxyl groups, which show much higher activity than the as‐generated β‐hydroxyls during curing, leading to enhanced dynamic properties of the EV. As a result, on the one hand, the EV achieves the UL‐94 V‐0 rating with a high limiting oxygen index value of 37.3%; and it shows a 41% reduction for the peak heat release rate and a 39% reduction for the total heat release in the cone calorimetry test. On the other hand, such EV exhibits rapid stress relaxation and is reprocessed easily to maintain its mechanical properties, thermal properties and flame retardancy to the hilt.

Supramolecular mineralization strategy for engineering covalent organic frameworks with superior Zn-I2 battery performances

•A supramolecular mineralization strategy for constructing COFs is proposed •The strategy holds a generality by modulating different assembly blocks •PY-2PBA COF features strong I2 adsorption and accompanying increased conductivity •The engineered PY-2PBA COF delivers impressive performances in Zn-I2 batteries Construction of covalent organic frameworks (COFs) with fine-tuning pore structures and crystalline orientations at the nano-/meso-scale is vital for their potential applications, but common synthesis routes for COFs always result in the unpredictable nucleation growth and aggregation of small crystals with arbitrary orientations and geometries. Here, we develop a supramolecular mineralization strategy for controllable fabrication of semiconducting COF nanoarchitectures by pre-assembly and subsequent in situ covalent locking of supramolecules. This strategy allows us to change the dynamic covalent chemistry reaction path by reducing the entropy of the system, thus facilitating control over the growth and crystallization of COFs on demand (including 1D, 2D, etc.). The tailor-made COF can effectively suppress the shuttle effect and accelerate the conversion of polyiodide through strong intrinsic electron-pair induce interactions, thereby delivering an outstanding performance in zinc-iodine batteries. The studies create a link between supramolecular chemistry and polymer science for the controllable construction of COF and supramolecular materials. Construction of covalent organic frameworks (COFs) with fine-tuning pore structures and crystalline orientations at the nano-/meso-scale is vital for their potential applications, but common synthesis routes for COFs always result in the unpredictable nucleation growth and aggregation of small crystals with arbitrary orientations and geometries. Here, we develop a supramolecular mineralization strategy for controllable fabrication of semiconducting COF nanoarchitectures by pre-assembly and subsequent in situ covalent locking of supramolecules. This strategy allows us to change the dynamic covalent chemistry reaction path by reducing the entropy of the system, thus facilitating control over the growth and crystallization of COFs on demand (including 1D, 2D, etc.). The tailor-made COF can effectively suppress the shuttle effect and accelerate the conversion of polyiodide through strong intrinsic electron-pair induce interactions, thereby delivering an outstanding performance in zinc-iodine batteries. The studies create a link between supramolecular chemistry and polymer science for the controllable construction of COF and supramolecular materials.

Dynamic Covalent Reactions and Chirality Sensing with Diphenylethene Derived Hemiaminals.

The differentiation of enantiomers is of significance in synthetic chemistry and pharmaceutical chemistry. Herein, we report a facile method for chirality sensing of monoalcohols, a challenging target due to the poor reactivity, by combining dynamic covalent chemistry with helical chirality. Four diphenylethene (DPE) derived cyclic hemiaminals were constructed, and the incorporation of a broad range of alcohols and thiols with high efficiency was achieved. The reversibility was further verified by dynamic component exchange. The helical chirality of the DPE motif was induced through chirality transfer by the central chirality of the analytes, resulting in circular dichroism responses. The chirality differentiation of seven chiral secondary alcohols including both alkyl and aryl alcohols was realized, further allowing the quantification of enantiomeric excess with high accuracy. The results described should lay a foundation for future endeavors in chemical sensing, asymmetric synthesis, and chiroptical materials.

N-Sulfonyl Urethanes to Design Polyurethane Networks with Temperature-Controlled Dynamicity

(Re)processing of cross-linked polyurethanes (PUs) is often energy intensive and inefficient since dissociation of urethane linkages at elevated temperatures generates highly reactive isocyanate moieties that can react with a wide range of nucleophiles. In this study, we first show with a small molecule study that the introduction of N-sulfonyl urethane bonds leads to dynamic covalent exchange reactions under much milder conditions compared to regular urethane groups. Then, these exchangeable N-sulfonyl urethane motifs have been introduced, in relatively small amounts (5, 10, and 20%), in a cross-linked PU matrix in an attempt to facilitate plastic flow at lower temperatures. Rheological analysis of the elastomeric dissociative networks revealed an interesting double relaxation behavior, even for temperatures between 150 and 100 °C, which could be described by a Maxwell model with two elements, which can be related to the activated and less activated urethane bonds. Finally, the (re)processability of these sulfonyl urethanes containing PUs was demonstrated through multiple cutting and hot pressing cycles and the corresponding materials showed a good retention of thermal properties.

Immunoinducible Carbon Dot-Incorporated Hydrogels as a Photothermal-Derived Antigen Depot to Trigger a Robust Antitumor Immune Response.

Immunogenic tumor cell death (ICD) induced by photothermal therapy (PTT) fails to elicit a robust antitumor immune response partially due to its inherent immunosuppressive microenvironment and poor antigen presentation. To address these issues, we developed an immunoinducible carbon dot-incorporated hydrogel (iCD@Gel) through a dynamic covalent Schiff base reaction using mannose-modified aluminum-doped carbon dots (M/A-CDs) as a cross-linking agent. The M/A-CDs possessed superior photothermal conversion efficiency and served as nanocarriers to load cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs) for inducing the maturation of dendritic cells (DCs) via mannose receptor-mediated targeting delivery. Upon intratumoral injection, the as-prepared iCD@Gel induced ICD, and damage-associated molecular patterns (DAMPs) were released via photothermal ablation under 808 nm NIR irradiation. Subsequently, the iCD@Gel synergized with the DAMPs to significantly promote the maturation and antigen cross-presentation ability of DCs. This work provides a promising strategy to develop carbon dot-based therapeutic hydrogels for photothermal therapy and immune activation.