Dynamic combinatorial chemistry

Dynamic combinatorial chemistry (DCC; also known as dynamic covalent chemistry) is a method to the generation of new molecules formed by reversible reaction of simple building blocks under thermodynamic control. The library of these reversibly interconverting building blocks is called a dynamic combinatorial library (DCL). All constituents in a DCL are in equilibrium, and their distribution is determined by their thermodynamic stability within the DCL. The interconversion of these building blocks may involve covalent or non-covalent interactions. When a DCL is exposed to an external influence (such as proteins or nucleic acids), the equilibrium shifts and those components that interact with the external influence are stabilised and amplified, allowing more of the active compound to be formed.

By modern definition, dynamic combinatorial chemistry is generally considered to be a method of facilitating the generation of new chemical species by the reversible linkage of simple building blocks, under thermodynamic control. This principle is known to select the most thermodynamically stable product from an equilibrating mixture of a number of components, a concept commonly utilised in synthetic chemistry to direct the control of reaction selectivity. Although this approach was arguably utilised in the work of Fischer and Werner as early as the 19th century, their respective studies of carbohydrate and coordination chemistry were restricted to rudimentary speculation, requiring the rationale of modern thermodynamics. It was not until supramolecular chemistry revealed early concepts of molecular recognition, complementarity and self-organisation that chemists could begin to employ strategies for the rational design and synthesis of macromolecular targets. The concept of template synthesis was further developed and rationalised through the pioneering work of Busch in the 1960s, which clearly defined the role of a metal ion template in stabilising the desired ‘thermodynamic’ product, allowing for its isolation from the complex equilibrating mixture. Although the work of Busch helped to establish the template method as a powerful synthetic route to stable macrocyclic structures, this approach remained exclusively within the domain of inorganic chemistry until the early 1990s, when Sanders et al. first proposed the concept of dynamic combinatorial chemistry. Their work combined thermodynamic templation in tandem with combinatorial chemistry, to generate an ensemble complex porphyrin and imine macrocycles using a modest selection of simple building blocks.

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