1
Principles of Dynamic Covalent Chemistry

Fredrik Schaufelberger, Brian J.J. Timmer, and Olof Ramström

1.1 Introduction

1.1.1 What is Dynamic Covalent Chemistry?

A key feature in supramolecular chemistry is its dynamic nature. The weak non-covalent bonds utilized are labile and reversible, and supramolecular systems spontaneously organize into the thermodynamically most preferred composition. However, the same inherent instability of supramolecular assemblies precludes their use in many applications where a higher degree of robustness is required. Thus, a demand for a set of reactions that combine the dynamic properties of supramolecular chemistry with the stability and robustness of covalent bonds arose. To meet this requirement, dynamic covalent chemistry (DCvC*) was developed.[1-3] This chemistry is based on reversible covalent bonds and extends traditional supramolecular chemistry into the molecular domain. The resulting combination gives rise to constitutional dynamic chemistry (CDC), a type of chemistry where the molecular constitution of a chemical system may undergo changes over time or in response to stimuli (Figure 1.1).[4] In this context, the generation of mixtures of interconverting constituents can lead to compound collections, representing a sub-field of CDC normally termed dynamic combinatorial chemistry (DCC).[2,5]

Figure 1.1 Overview of the structural order of dynamic chemistry.

Dynamic covalent chemistry is not a new concept and its origins can be traced back to the roots of chemistry.[6] Fundamental discoveries in the field were made by, for example, Williamson, Schiff, and Fischer, and the concept of reversible covalent bonds was also discussed by Werner during investigations of metal-ligand coordination. An early application of the concept in template synthesis was reported in the 1920s by Seidel, where macrocyclization of 2-aminobenzaldehyde in the presence of ZnCl2 resulted in an unidentified structure that was later identified as a tetrameric macrocycle (Scheme 1.1).[7,8]

Scheme 1.1 Template-assisted macrocyclization of 2-aminobenzaldehyde under thermodynamic control.

The field of DCvC has, however, evolved rapidly in recent years and today reversible covalent bonds are utilized in a plethora of applications (Figure 1.2).[9,10] DCvC has found extensive use in, for example, materials science, nanochemistry, catalysis, surface chemistry, chemical biology, and analytical sensing.[11-16]

Figure 1.2 Selected applications of dynamic covalent chemistry.

In this chapter, the underlying features of dynamic covalent chemistry are described, followed by a short exposé over the toolbox of reversible covalent reactions available today. Furthermore, some of the analytical challenges in DCvC are briefly highlighted.

1.1.2 Importance of Dynamic Covalent Chemistry

Dynamic covalent bonds are ubiquitous in nature, and they are continuously being utilized in biotic settings to provide a wide range of functions. For example, reversible disulfide chemistry controls protein folding and thus the self-assembly of polypeptides into ternary structures, dynamic imines are integral for human vision, reversible thioesters are key players in our metabolic pathways, and dynamic covalent enone chemistry is a reason why red peppers are so pungent.[17]

Furthermore, DCvC provides an entry into the design of complex systems capable of continuous adaptation and evolution. Creating function by design is a central objective in chemistry, and dynamic covalent bonds provide access to systems capable of self-sorting, replication, adaptation towards selection pressures, self-healing, and the construction of highly complex molecular architectures. Some macrocyclic/cage molecules synthesized through DCvC approaches are displayed in Figure 1.3. The Solomon link (left), prism (middle), and nanocapsule (right) all represent structures that would be difficult to access without DCvC.[18-20]

Figure 1.3 Examples of complex macrocyclic/cage structures created through dynamic covalent chemistry.

Since dynamic covalent chemistry operates under thermodynamic control, it allows a system of components (building blocks) and/or constituents (products) to settle into its thermodynamically most favorable state. Thus, the information stored in the molecular components of a system can be expressed with high precision and a high degree of "proof-reading", giving access to the optimal molecular architectures for a given setting. In comparison with "static", non-dynamic chemistry, DCvC thus relies on the inherent molecular information in the system. Since any constituent created during a synthesis utilizing reversible covalent bonds is eventually reprocessed, DCvC acts as a sort of error-correction, where non-optimal intermediates are recycled to form the thermodynamically more stable products.

1.1.3 Basic Concepts

Large dynamic systems (Figure 1.4) of interconverting molecular entities can be generated using DCvC. These systems undergo continuous exchange towards an equilibrium point through the information contained in either the molecules themselves or their surroundings.

Figure 1.4 Two alternative representations of a dynamic system with the components A, B, C, and D undergoing reversible exchange.

As mentioned, when the intrinsic dynamic nature of CDC is applied to large systems with collections of molecular entities, dynamic (DCLs) or virtual combinatorial libraries (VCLs) can be created, the latter representing situations where constituents remain unexpressed in the absence of stabilizing entities.[21-23]

A dynamic covalent bond is reversible and can be broken and reformed to eventually reach a thermodynamic equilibrium. Once this has been established, the molecular status quo can be disturbed if the system is perturbed by stimuli. For example, the constitution of dynamic systems can respond to changes in chemical environment (complexing entities, etc.) or physical conditions (temperature, mechanical stress, electric field, irradiation, etc.). This constitutional adaptation leads to the "evolution" of a more favorable thermodynamic system under the new conditions. For example, when a dynamic system is exposed to a target selector (e.g., ligand, receptor) that can selectively interact with one of the many interconverting substituents, the system can be perturbed. The transient stabilization of the best constituent by the target selector will cause re-equilibration of the system, ideally leading to amplification of the "fittest" compound at the expense of all other combinations. The concept can be illustrated through Emil Fischer's lock-and-key metaphor (Figure 1.5). Here, the keys are constructed from different dynamically reacting components, and the addition of a lock stabilizes and amplifies the key that best fits the keyhole. This type of "thermodynamic self-screening" is appealing for drug/ligand discovery applications, as the best binder can be directly identified from a large system by inspection of the component distribution before and after target addition. This circumvents the need for synthesis and purification as well as screening of each individual compound.

Figure 1.5 Illustration of the basic concept behind selection in dynamic covalent chemistry. The building blocks self-assemble into different "keys", and the key that best fits into the "lock" is amplified at the expense of the other keys.

1.2 The Dynamic Covalent Bond

1.2.1 Requirements for Dynamic Covalent Bonds

The most important criteria for dynamic covalent bonds are the covalent nature and the bond strengths. For some systems, a lifetime of each bond in the range 1?ms?<?t?<?1?min has been proposed to yield connections that are stable and detectable with most analytical methods, yet dynamic enough to allow swift adaptation.[9] This translates into equilibrium times in the order of hours to days for large dynamic systems. The upper limit of the equilibration time for a DCvC application is also related to the degradation stability of the components and constituents in the system, as equilibrium must be attained before the system starts degrading.

As covalent connections are intrinsically more stable than supramolecular interactions, dynamic covalent bonds are typically much more robust but also slower to exchange than the corresponding supramolecular interactions. Thus, most dynamic covalent bonds require some type of catalysis in order to promote exchange (discussed further in section 1.2.2).

For dynamic covalent bonds, mild reaction conditions are beneficial for preserving the integrity of the bond and to maintain delicate non-covalent interactions of interest in the system. The reactions should also be compatible with the application of interest, and resistance to moisture and oxygen is of general importance. For biological applications, a dynamic covalent bond should exchange readily in water or water/organic solvent mixtures, although only a few bonds obeying such criteria have been discovered. Note that a tradeoff between equilibration rates and...