Transient Substrate‐Induced Catalyst Formation in a Dynamic Molecular Network

In biology enzyme concentrations are continuously regulated, yet for synthetic catalytic systems such regulatory mechanisms are underdeveloped. We now report how a substrate of a chemical reaction induces the formation of its own catalyst from a dynamic molecular network. After complete conversion of the substrate, the network disassembles the catalyst. These results open up new opportunities for controlling catalysis in synthetic chemical systems.     

Dynamic Environments as a Tool to Preserve Desired Output in a Chemical Reaction Network

Current efforts to design functional molecular systems have overlooked the importance of coupling out-of-equilibrium behaviour with changes in the environment. Here, the authors use an oscillating reaction network and demonstrate that the application of environmental forcing, in the form of periodic changes in temperature and in the inflow of the concentration of one of the network components, removes the dependency of the periodicity of this network on temperature or flow rates and enforces a stable periodicity across a wide range of conditions. Coupling a system to a dynamic environment can thus be used as a simple tool to regulate the output of a network. In addition, the authors show that coupling can also induce an increase in behavioural complexity to include quasi-periodic oscillations.     

Dithioacetal Exchange: A New Reversible Reaction for Dynamic Combinatorial Chemistry

Reversibility of dithioacetal bond formation is reported under acidic mild conditions. Its utility for dynamic combinatorial chemistry was explored by combining it with orthogonal disulfide exchange. In such a setup, thiols are positioned at the intersection of both chemistries, constituting a connecting node between temporally separated networks.     

Dynamic Combinatorial Chemistry: A New Methodology Comes of Age

Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacologically relevant targets. Over time, the term tdDCC has been applied to describe a number of different experimental setups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for analysis and evaluation of experiments.     

Indirect Optical Analysis of a Dynamic Chemical System

Hide and seek : The composition of a dynamic covalent equilibrium reaction is determined by measuring the ‘left‐over’ concentration of a reference compound (blue object, see picture). Reaction of the reference compound with a scavenger generates a characteristic UV/Vis signal that is independent of the molecular structure of the target.

     

trans‐Symmetric Dynamic Covalent Systems: Connected Transamination and Transimination Reactions

The development of chemical transaminations as a new type of dynamic covalent reaction is described. The key 1,3‐proton shift is under complete catalytic control and can be conducted orthogonally to, or simultaneous with, transimination in the presence of an amine to rapidly yield two‐dimensional dynamic systems with a high degree of complexity evolution. The transamination–transimination systems are proven to be fully reversible, stable over several days, compatible with a range of functional groups, and highly tunable. Kinetic studies show transamination to be the rate‐limiting reaction in the network. Furthermore, it was discovered that readily available quinuclidine is a highly potent catalyst for aldimine transaminations. This study demonstrates how connected dynamic reactions give rise to significantly larger systems than the unconnected counterparts, and shows how reversible isomerizations can be utilized as an effective diversity‐generating element.     

Hydrogen-Bond Catalysis of Imine Exchange in Dynamic Covalent Systems

The reversibility of imine bonds has been exploited to great effect in the field of dynamic covalent chemistry, with applications such as preparation of functional systems, dynamic materials, molecular machines, and covalent organic frameworks. However, acid catalysis is commonly needed for efficient equilibration of imine mixtures. Herein, it is demonstrated that hydrogen bond donors such as thioureas and squaramides can catalyze the equilibration of dynamic imine systems under unprecedentedly mild conditions. Catalysis occurs in a range of solvents and in the presence of many sensitive additives, showing moderate to good rate accelerations for both imine metathesis and transimination with amines, hydrazines, and hydroxylamines. Furthermore, the catalyst proved simple to immobilize, introducing both reusability and extended control of the equilibration process.     

Complex Functional Systems with Three Different Types of Dynamic Covalent Bonds

Multicomponent surface architectures are introduced that operate with three different dynamic covalent bonds. Disulfide exchange under basic conditions accounts for the growth of π stacks on solid surfaces. Hydrazone exchange under acidic conditions is used to add a second coaxial string or stack, and boronic ester exchange under neutral conditions is used to co‐align a third one. The newly introduced boronic ester exchange chemistry is compatible with stack and string exchange without interference from the orthogonal hydrazone and disulfide exchange. The functional relevance of surface architectures with three different dynamic covalent bonds is exemplified with the detection of polyphenol natural products, such as epigallocatechin gallate, in competition experiments with alizarin red. These results describe synthetic strategies to create functional systems of unprecedented sophistication with regard to dynamic covalent chemistry.     

Interplay of Interactions Governing the Dynamic Conversions of Acyclic and Macrocyclic Helicates

Systemic change : A system of transformations between helical structures was observed to be governed by interactions mediated by the electronic effects of substituents, entropic effects, the conformational preferences of organic building blocks, and the coordinative preferences of the metal ion. All of these effects were important, but all must be considered together to allow the prediction of the product observed (see scheme).

     

Bond Scrambling and Network Elasticity

Dynamic networks (DNs) recently reported in the literature are based on cross‐linked supramolecular chains or on covalent chains with reversible bonds. As originally pointed out by Lehn, these networks should be regarded as dynamic materials exhibiting adaptive features due to continuous scrambling of their bonds and sequences. Results in the recent literature reveal that these networks undergo reversible long‐range deformation resembling that of rubber networks. The present analysis of this process in terms of the theory of composite networks is based on the expectation that the scrambling process should allow rupture of bonds in the undeformed state and their reformation in the stretched state. Accordingly, a permanent set of the resting length of DNs should generally be expected and set materials should retain long‐range elasticity relative to the set state. However, only a limited set is shown by DNs, implying that a strong memory of the initial network topology assists elastic recovery of the original dimensions. The analysis of reported experimental data further reveals that the stress‐strain dependence of dynamic networks accurately follows the classical rubber elasticity theory. In this respect, DNs show better rubber behavior than typical covalent networks. Consistently with theoretical predictions, this surprising finding suggests that bond scrambling relieves local strain constraints on the fluctuations of networks junctions and favors the recovery of the initial network topology. Scrambling therefore allows compliance under stress and enhanced recovery when stress is released. Unprecedented applications of these advanced materials thus become foreseeable.     

Tunable Orthogonal Reversible Covalent (TORC) Bonds: Dynamic Chemical Control over Molecular Assembly

Dynamic assembly of macromolecules in biological systems is one of the fundamental processes that facilitates life. Although such assembly most commonly uses noncovalent interactions, a set of dynamic reactions involving reversible covalent bonding is actively being exploited for the design of functional materials, bottom‐up assembly, and molecular machines. This Minireview highlights recent implementations and advancements in the area of tunable orthogonal reversible covalent (TORC) bonds for these purposes, and provides an outlook for their expansion, including the development of synthetically encoded polynucleotide mimics.     

Adsorption‐Driven Self‐Sorting of Dynamic Imine Libraries

Differences in adsorption among the components of complex mixtures play a role in separations, surface‐based sensing, and heterogeneous catalysis, and have been implicated in theories of the origin of life. Herein, we consider mixtures of imines and we show that if such complex mixtures are also dynamic—that is, if their components equilibrate among themselves—then they can dramatically simplify in composition during the course of column chromatography. As they travel down the column, imines continuously trade their aldehyde and amine constituents, favoring the formation of molecules with extremes of polarity at the expense of species with intermediate polarities. Iterative application of this principle leads to simplification of imine libraries containing up to 16 members into 4 major products.     

Tuning the Outcome of Enzyme-Mediated Dynamic Cyclodextrin Libraries to Enhance Template Effects

Enzyme-mediated dynamic combinatorial chemistry combines the concept of thermodynamically controlled covalent self-assembly with the inherent biological relevance of enzymatic transformations. A system of interconverting cyclodextrins has been explored, in which the glycosidic linkage is rendered dynamic by the action of cyclodextrin glucanotransferase (CGTase). External factors, such as pH, temperature, solvent, and salinity are reported to modulate the composition of the dynamic cyclodextrin library. Dynamic libraries of cyclodextrins (CDs) could be obtained in wide ranges of pH (5.0–9.0), temperature (5–37 °C), and salinity (up to 7.5 m NaNO₃), and with high organic solvent content (50 % by volume of ethanol), showing that enzyme-mediated dynamic systems can be robust and not limited to physiological conditions. Furthermore, it is demonstrated how strategic choice of reaction conditions can enhance template effects, in this case, to achieve highly selective production of α-CD, an otherwise challenging target due to competition from the structurally similar β-CD.