Reversible Covalent Bond Formation Research Articles

Reconstruction of Covalent Organic Frameworks by Dynamic Equilibrium.

Covalent organic frameworks (COFs) are periodic two- or three-dimensional polymeric networks with high surface areas, low density, and designed structures. Because COFs are normally prepared based on reversible formation of covalent bonds with relatively weak stability, their structures can be easily broken or damaged due to changes in the surrounding environment. Thus, developing strategies to realize the reconstruction of COFs in order to extend their usage lifetime is crucial for practical applications. In addition, exploring the kinetics of COF growth under varied reaction conditions is important for better understanding the nucleation and growth processes of COFs. In this work, the reformation mechanism of an imine-based COF using an ex situ characterization method was investigated, disclosing an interesting COF reconstruction progress from disorder to order. The present study shows the regeneration ability of COFs, and the developed method could be generalized for broader use in the field.

Calcium-Catalyzed Dynamic Multicomponent Reaction.

The reversible formation of covalent bonds enabled by the remarkably high Lewis acidity of our calcium-based catalyst system was used for the development of a new type of multicomponent reaction. Accordingly, a pharmacologically interesting bicyclic amine was amplified from a highly efficient dynamic equilibrium. The product is formed with full diastereoselectivity, and as typical for our calcium-catalyzed reactions, precautions for the exclusion of air and moisture are unnecessary.

Artificial Molecular Machines.

The widespread use of molecular machines in biology has long suggested that great rewards could come from bridging the gap between synthetic molecular systems and the machines of the macroscopic world. In the last two decades, it has proved possible to design synthetic molecular systems with architectures where triggered large amplitude positional changes of submolecular components occur. Perhaps the best way to appreciate the technological potential of controlled molecular-level motion is to recognize that nanomotors and molecular-level machines lie at the heart of every significant biological process. Over billions of years of evolution, nature has not repeatedly chosen this solution for performing complex tasks without good reason. When mankind learns how to build artificial structures that can control and exploit molecular level motion and interface their effects directly with other molecular-level substructures and the outside world, it will potentially impact on every aspect of functional molecule and materials design. An improved understanding of physics and biology will surely follow. The first steps on the long path to the invention of artificial molecular machines were arguably taken in 1827 when the Scottish botanist Robert Brown observed the haphazard motion of tiny particles under his microscope.1,2 The explanation for Brownian motion, that it is caused by bombardment of the particles by molecules as a consequence of the kinetic theory of matter, was later provided by Einstein, followed by experimental verification by Perrin.3,4 The random thermal motion of molecules and its implications for the laws of thermodynamics in turn inspired Gedankenexperiments (“thought experiments”) that explored the interplay (and apparent paradoxes) of Brownian motion and the Second Law of Thermodynamics. Richard Feynman’s famous 1959 lecture “There’s plenty of room at the bottom” outlined some of the promise that manmade molecular machines might hold.5,6 However, Feynman’s talk came at a time before chemists had the necessary synthetic and analytical tools to make molecular machines. While interest among synthetic chemists began to grow in the 1970s and 1980s, progress accelerated in the 1990s, particularly with the invention of methods to make mechanically interlocked molecular systems (catenanes and rotaxanes) and control and switch the relative positions of their components.7−24 Here, we review triggered large-amplitude motions in molecular structures and the changes in properties these can produce. We concentrate on conformational and configurational changes in wholly covalently bonded molecules and on catenanes and rotaxanes in which switching is brought about by various stimuli (light, electrochemistry, pH, heat, solvent polarity, cation or anion binding, allosteric effects, temperature, reversible covalent bond formation, etc.). Finally, we discuss the latest generations of sophisticated synthetic molecular machine systems in which the controlled motion of subcomponents is used to perform complex tasks, paving the way to applications and the realization of a new era of “molecular nanotechnology”. 1.1. The Language Used To Describe Molecular Machines Terminology needs to be properly and appropriately defined and these meanings used consistently to effectively convey scientific concepts. Nowhere is the need for accurate scientific language more apparent than in the field of molecular machines. Much of the terminology used to describe molecular-level machines has its origins in observations made by biologists and physicists, and their findings and descriptions have often been misinterpreted and misunderstood by chemists. In 2007 we formalized definitions of some common terms used in the field (e.g., “machine”, “switch”, “motor”, “ratchet”, etc.) so that chemists could use them in a manner consistent with the meanings understood by biologists and physicists who study molecular-level machines.14 The word “machine” implies a mechanical movement that accomplishes a useful task. This Review concentrates on systems where a stimulus triggers the controlled, relatively large amplitude (or directional) motion of one molecular or submolecular component relative to another that can potentially result in a net task being performed. Molecular machines can be further categorized into various classes such as “motors” and “switches” whose behavior differs significantly.14 For example, in a rotaxane-based “switch”, the change in position of a macrocycle on the thread of the rotaxane influences the system only as a function of state. Returning the components of a molecular switch to their original position undoes any work done, and so a switch cannot be used repetitively and progressively to do work. A “motor”, on the other hand, influences a system as a function of trajectory, meaning that when the components of a molecular motor return to their original positions, for example, after a 360° directional rotation, any work that has been done is not undone unless the motor is subsequently rotated by 360° in the reverse direction. This difference in behavior is significant; no “switch-based” molecular machine can be used to progressively perform work in the way that biological motors can, such as those from the kinesin, myosin, and dynein superfamilies, unless the switch is part of a larger ratchet mechanism.14

Porous Solids Arising from Synergistic and Competing Modes of Assembly: Combining Coordination Chemistry and Covalent Bond Formation

AbstractDesign and synthesis of porous solids employing both reversible coordination chemistry and reversible covalent bond formation is described. The combination of two different linkage modes in a single material presents a link between two distinct classes of porous materials as exemplified by metal–organic frameworks (MOFs) and covalent organic frameworks (COFs). This strategy, in addition to being a compelling material‐discovery method, also offers a platform for developing a fundamental understanding of the factors influencing the competing modes of assembly. We also demonstrate that even temporary formation of reversible connections between components may be leveraged to make new phases thus offering design routes to polymorphic frameworks. Moreover, this approach has the striking potential of providing a rich landscape of structurally complex materials from commercially available or readily accessible feedstocks.

Dynamic covalent chemistry of bisimines at the solid/liquid interface monitored by scanning tunnelling microscopy.

Dynamic covalent chemistry relies on the formation of reversible covalent bonds under thermodynamic control to generate dynamic combinatorial libraries. It provides access to numerous types of complex functional architectures, and thereby targets several technologically relevant applications, such as in drug discovery, (bio)sensing and dynamic materials. In liquid media it was proved that by taking advantage of the reversible nature of the bond formation it is possible to combine the error-correction capacity of supramolecular chemistry with the robustness of covalent bonding to generate adaptive systems. Here we show that double imine formation between 4-(hexadecyloxy)benzaldehyde and different α,ω-diamines as well as reversible bistransimination reactions can be achieved at the solid/liquid interface, as monitored on the submolecular scale by in situ scanning tunnelling microscopy imaging. Our modular approach enables the structurally controlled reversible incorporation of various molecular components to form sophisticated covalent architectures, which opens up perspectives towards responsive multicomponent two-dimensional materials and devices.

Dynamic combinatorial/covalent chemistry: a tool to read, generate and modulate the bioactivity of compounds and compound mixtures

Reversible covalent bond formation under thermodynamic control adds reactivity to self-assembled supramolecular systems, and is therefore an ideal tool to assess complexity of chemical and biological systems. Dynamic combinatorial/covalent chemistry (DCC) has been used to read structural information by selectively assembling receptors with the optimum molecular fit around a given template from a mixture of reversibly reacting building blocks. This technique allows access to efficient sensing devices and the generation of new biomolecules, such as small molecule receptor binders for drug discovery, but also larger biomimetic polymers and macromolecules with particular three-dimensional structural architectures. Adding a kinetic factor to a thermodynamically controlled equilibrium results in dynamic resolution and in self-sorting and self-replicating systems, all of which are of major importance in biological systems. Furthermore, the temporary modification of bioactive compounds by reversible combinatorial/covalent derivatisation allows control of their release and facilitates their transport across amphiphilic self-assembled systems such as artificial membranes or cell walls. The goal of this review is to give a conceptual overview of how the impact of DCC on supramolecular assemblies at different levels can allow us to understand, predict and modulate the complexity of biological systems.

A Highly Efficient and Visualized Method for Glycan Enrichment by Self-Assembling Pyrene Derivative Functionalized Free Graphene Oxide

Protein glycosylation plays key roles in many biological processes, such as cell growth, differentiation, and cell-cell recognition. Therefore, global structure profiling of glycans is very important for investigating the biological significance and roles of glycans in disease occurrence and development. Mass spectrometry (MS) is currently the most powerful technique for structure analysis of oligosaccharides, but the limited availability of glycan/glycoproteins from natural sources restricts the wide adoption of this technique in large-scale glycan profiling. Though various enrichment methods have been developed, most methods relay on the weak physical affinity between glycans and adsorbents that yields insufficient enrichment efficiency. Furthermore, the lack of monitoring the extent/completeness of enrichment may lead to incomplete enrichment unless repeated sample loading and prolonged incubation are adopted, which limits sample handling throughput. Here, we report a rapid, highly efficient, and visualized approach for glycan enrichment using 1-pyrenebutyryl chloride functionalized free graphene oxide (PCGO). In this approach, glycan capturing is achieved by reversible covalent bond formation between the hydroxyl groups of glycans and the acyl chloride groups on graphene oxide (GO) introduced by π-π stacking of 1-pyrenebutyryl chloride on the GO surface. The multiple hydroxyl groups of glycans lead to cross-linking and self-assembly of free PCGO sheets into visible aggregation within 30 s, therefore achieving simple visual monitoring of the enrichment process. Improved enrichment efficiency is achieved by the large specific surface area of free PCGO and heavy functionalization of highly active 1-pyrenebutyryl chloride. Application of this method in enrichment of standard oligosaccharides or N-glycans released from glycoproteins results in remarkably increased MS signal intensity (approximately 50 times), S/N, and number of glycoform identified.

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.

Regulation of cell proliferation by multi-layered phospholipid polymer hydrogel coatings through controlled release of paclitaxel

We fabricated multi-layered hydrogels on titanium alloy (Ti) surfaces by applying alternating layers of a water-soluble phospholipid polymer (PMBV) and polyvinyl alcohol (PVA). This was accomplished by a layer-by-layer (LbL) process that is based on the formation of reversible covalent bonds between the boronic acid subunits in the PMBV and the hydroxyl groups in the PVA. When placed in an aqueous medium, PMBV acquires a polymeric aggregate structure with hydrophobic domains that can effectively solubilize hydrophobic molecules such as the anticancer drug paclitaxel (PTX) used in this study. The PTX-containing PMBV layer acted as a reservoir in the multi-layered hydrogels. To obtain diverse release profiles, the PTX was loaded in either the top layer (top-type) or the bottom layer (bottom-type) of the hydrogels; additional layers of PMBV and PVA, without PTX, functioned as a diffusion-barrier. In cell culture experiments, top-type hydrogels demonstrated excessive suppression of human epidermal carcinoma A431 cell proliferation over 5 days due to the initial high concentration of released PTX. However, bottom-type hydrogels were able to maintain a constant cell number profile. The release of PTX from multi-layered hydrogels was governed by both diffusion through the diffusion-barrier and dissociation of the hydrogel through an exchange reaction of phenylboronic acid subunits with the low-molecular weight d-glucose in the cell culture medium. In the cell culture experiments, the cell cycle was arrested in S and G2/M phases, as expected following PTX-mediated growth inhibition; control hydrogels did not demonstrate any appreciable cell cycle arrest. We concluded that cell proliferation could be controlled by the concentration of PTX released from the multi-layered hydrogels prepared through the LbL process. This system when used to solubilize bioactive agents at an appropriate layer within the hydrogel has potential for localized and surface-mediated delivery of bioactive molecules from biomedical devices.

Fabrication of multi-responsive interpolymer complex micelles via reversible covalent bond formation between phenylboronic acid and glucose moieties

Two types of diblock copolymers containing phenylboronic acid and glucose moieties,respectively,poly(N-isopropylacrylamide)-b-poly(N-acryloyl-3-aminophenylboronic acid)(PNIPAM-b-PAPBA) and poly(N-isopropylacrylamide)-b-poly(acryloyl glucosamine)(PNIPAM-b-PAGA) were synthesized via reversible addition-fragmentation chain transfer(RAFT) polymerization.Due to the formation of borate ester functionalities between phenylboronic acid and glucose moieties under slightly alkaline conditions(pH 9.3),mixed solution of PNIPAM-b-PAPBA and PNIPAM-b-PAGA diblock copolymers can spontaneously form interpolymer complex micelles consisting of PAPBA/PAGA complex cores and PNIPAM coronas.Since the formation/cleavage of borate ester linkages is highly reversible upon the variation of solution pH and glucose concentrations,interpolymer complex micelles fabricated via reversible covalent bond formation between PAPBA and PAGA blocks exhibit multi-responsiveness to pH,glucose and temperature.

ChemInform Abstract: Integrating Replication‐Based Selection Strategies in Dynamic Covalent Systems.

AbstractReview: [35 refs.]

Integrating Replication‐Based Selection Strategies in Dynamic Covalent Systems

In the past 15 years, the chemistry of reversible covalent bond formation (dynamic covalent chemistry (DCC)) has been exploited to engineer networks of interconverting compounds known as dynamic combinatorial libraries (DCLs). Classically, the distribution of library components is governed by their relative free energies, and so, processes that manipulate the free energy landscape of the DCL can influence the distribution of library members. Within the same time frame, the design and implementation of molecules capable of copying themselves--so-called replicators--has emerged from the field of template-directed synthesis. Harnessing the nonlinear kinetics inherent in replicator behavior offers an attractive strategy for amplification of a target structure within a DCL and, hence, engendering high levels of selectivity within that library. The instructional nature of replicating templates also renders the combination of replication and DCC a potential vehicle for developing complex reaction networks; a prerequisite for the development of the emerging field of systems chemistry. This Concept article explores the role of kinetically and thermodynamically controlled processes within different DCC frameworks. The effects of embedding a replicating system within these DCC frameworks is explored and the consequences of the different topologies of the reaction network for amplification and selectivity within DCLs is highlighted.

Linking rings without templates

Interlocking molecules in solution usually requires recognition motifs that direct the assembly of the building blocks. Triply interlocked catenanes have now been constructed just relying on the interpenetration of structures typical of the solid state and slow reversible covalent bond formation.

Molecular recognition of organic ammonium ions in solution using synthetic receptors.

Ammonium ions are ubiquitous in chemistry and molecular biology. Considerable efforts have been undertaken to develop synthetic receptors for their selective molecular recognition. The type of host compounds for organic ammonium ion binding span a wide range from crown ethers to calixarenes to metal complexes. Typical intermolecular interactions are hydrogen bonds, electrostatic and cation–π interactions, hydrophobic interactions or reversible covalent bond formation. In this review we discuss the different classes of synthetic receptors for organic ammonium ion recognition and illustrate the scope and limitations of each class with selected examples from the recent literature. The molecular recognition of ammonium ions in amino acids is included and the enantioselective binding of chiral ammonium ions by synthetic receptors is also covered. In our conclusion we compare the strengths and weaknesses of the different types of ammonium ion receptors which may help to select the best approach for specific applications.

Supramolecular interactions in chemomechanical polymers.

Molecular recognition is the basis for the operation of most biological functions; outside of nature, it has also been developed to a high degree of sophistication within the framework of supramolecular chemistry. More recently, selective noncovalent interactions, which constitute molecular recognition, are being used in intelligent new materials that transform chemical signals into actions, such as the release of drugs. The presence of supramolecular binding sites allows chemomechanical polymers to operate as sensors and actuators within a single unit without the need for any additional devices such as transducers or power supplies. A polymer can be designed so that a particular chemical substance, most often in aqueous surroundings, will trigger either a large expansion or a large contraction, depending on the mechanism. The translation of binding energy into mechanical motion can, with a suitable arrangement of the materials in tubes or on flexible films, be harnessed for unidirectional drives, flow control, the liberation of drugs, or the uptake of toxic compounds, among other applications. Miniaturization of the polymer particles allows one to enhance both the sensitivity and speed of the response, which is of particular importance in sensing. The basis for the selective response to external effector compounds, such as metal ions, amino acids, peptides, or nucleotides, is their noncovalent interaction with complementary functions covalently bound to the polymer network. With suitable polymers, selectivity between structural isomers, and even between enantiomers, as triggers can be achieved. As with supramolecular complexes in solution, the underlying interactions in polymers comprise a variety of noncovalent binding mechanisms, which are not easy to distinguish and quantify, and more so with polymers that are not monodisperse. In this Account, we present systematic comparisons of different polymers and effector classes that allow, for the first time, the characterization of these contributions in chemomechanical polymers: they comprise ion pairing, metal coordination, stacking, cation-pi, dispersive, and hydrophobic forces. In contrast, hydrogen bonding has a major role primarily in the hydrogel network structure itself. The fully reversible polymer volume changes are essentially determined by water uptake or release. In gels derived from boronic acid, glucose can serve as a cross-linking effector in promoting contractions via strong, reversible covalent bond formation in a highly distinctive manner. Cooperativity between two different effector compounds is more frequently seen with such polymers than in solution: it leads to logical AND gates by different motions of the particles, with a direct communication link to the outside world. For example, with a polymer that bears several recognition sites, triggering peptides induce motion only if Zn(2+) or Cu(2+) ions are simultaneously present. The molecular recognition mechanisms that cause volume changes in polymers share similarities with extensively studied supramolecular systems in solution, but there are also remarkable differences. In this Account, we bring the knowledge learned from solution studies to bear on our systematic analysis of polymeric systems in an effort to promote the effective harnessing of the forces involved in chemomechanical polymers and the smart materials that can be created with them.

Reversible Covalent Patterning of Self-Assembled Monolayers on Gold and Silicon Oxide Surfaces

This paper describes the generation of reversible patterns of self-assembled monolayers (SAMs) on gold and silicon oxide surfaces via the formation of reversible covalent bonds. The reactions of (patterned) SAMs of 11-amino-1-undecanethiol (11-AUT) with propanal, pentanal, decanal, or terephthaldialdehyde result in dense imine monolayers. The regeneration of these imine monolayers to the 11-AUT monolayer is obtained by hydrolysis at pH 3. The (patterned) monolayers were characterized by Fourier transform infrared reflection absorption spectroscopy, X-ray photoelectron spectroscopy, contact angle and electrochemical measurements, and atomic force microscopy. Imines can also be formed by microcontact printing of amines on terephthaldialdehyde-terminated substrates. Lucifer Yellow ethylenediamine was employed as a fluorescent amine-containing marker to visualize the reversible covalent patterning on a terephthaldialdehyde-terminated glass surface by confocal microscopy. These experiments demonstrate that with reversible covalent chemistry it is possible to print and erase chemical patterns on surfaces repeatedly.

Enzyme inhibition as a source of new drugs

AbstractThe significance of enzymes as targets of drug action is discussed. New approaches to the rational design of enzyme inhibitors are characterized by a pronounced shift of emphasis toward the targets of drug action, as the structure and function of an increasing number of enzymes are described in great detail. The most promising of the recently developed approaches is the design of mechanism‐based enzyme inhibitors and, in particular, suicide inactivators. These require enzymic activation of “latent” functional groups to chemically reactive species. The various functionalities currently encountered are reviewed, grouped into chemical categories.The various aspects of the selectivity and the specificity of mechanism‐based enzyme inhibitors, as well as the stability of drug‐enzyme complexes, are discussed in detail. Reversible covalent bond formation is demonstrated by the recovery of thymidylate synthetase activity after inactivation by various 5‐substituted pyrimidine analogs, using purified bacterial enzyme preparations or intact mammalian cells. The fragmentation and secondary reactions of the inhibitor within the complex are described using typical examples of the action of penicillin on its targets and clavulanate on /3‐lactamase, respectively.The perspectives of enzyme inhibitory drug development are discussed, and some of the many areas currently undergoing rapid exploration are mentioned.It is concluded that the rational design of enzyme inhibitors will play an ever‐increasing and significant role in new drug discovery and development.

Histone-histone propinquity by aldehyde fixation of chromatin.

Histones have been fixed within the chromatin complex using either formaldehyde or glutaraldehyde. Evidence is presented which argues that in short time periods formaldehyde fixation leads to the formation of reversible covalent bonds between histone and DNA. On the other hand, fixation of chromatin with glutaraldehyde leads initially to the formation of polymers of F1 histone, and at a later stage of multiple small oligomers of the remaining histones. There oligomers then increase in size until they become too large to detect by polyacrylamide gel electrophoresis. Exclusive formation of histone dimers or tetramers was not observed. The simplest model for histone distribution on DNA which encompasses these observations is one in which histones are organized as a fairly extensive linear overlapping array.