Dynamic combinatorial libraries thermodynamic

Chemical templates are being increasingly employed for the development of dynamic combinatorial libraries (DCL) [94-98]. These (virtual) libraries of compounds are produced from all the possible combinations of a set of basic components that can reversibly react with each other with the consequent potential to generate a large pool of compounds. Because of the dynamic equilibria established in a DCL, the stabilization of any given compound by molecular recognition will amplify its formation. Hence the addition of a template to the library usually leads to the isolation of the compound that forms the thermodynamically more stable host-guest complex (see Scheme 37). 

Polyakov VA, Nelen MI, Nazarpack-Kandlousy N, Ryabov AD, Eliseev AV. Imine exchange in 0-aryl and 0-alkyl oximes as a base reaction for aqueous dynamic combinatorial libraries. A kinetic and thermodynamic study. J Phys Org Chem 1999 12 357-363. 

Certain ligand structures are certain to be favored, and others not present at all ( virtual ) [26]. Likewise, certain metal complexes are thermodynamically more stable than others. Since dynamic interconversion is possible on both covalent and supramolecular levels, both ligand and metal preferences may act in concert to amplify a limited subset of structures out of the dynamic library of all possible structures. The preparation of 1 thus represents a sorting of the dynamic combinatorial library of Figure 1.2. 

Fig. 27 Examples of thermodynamically controlled reactions employed in the near-quantitative synthesis of MIMs. (a) Disulfide-exchange reaction permits equilibration between a bis(ammo-nium) disulfide dumbbell and a crown ether macrocycle to yield a mixture of [2]- and [3]rotaxanes quantitatively [194], (b) Olefin metathesis at high concentration on a benzylic amide macrocycle greatly favors the catenated species [196]. (c) Self-correcting imine bonds allow for nearly quantitative selection of a [2]rotaxane from an appropriate dynamic combinatorial library [76], (d) A weak nucleophile (E) equilibrates the components of a donor-acceptor [2]catenane in a dynamic Sn2 reaction [205]...

A dynamic combinatorial library of six components can be generated under thermodynamic control by imine formation and exchange combined with non-covalent bonding within the enzyme binding site and DCL was evaluated for their relative affinities toward the physiologically relevant human carbonic anhydrase hCA I and hCA II isozymes [66]. 

Dynamic combinatorial chemistry (DCC) is founded on the study and the construction of mixtures of discrete constituents which are produced by reversible molecular or supramolecular associations [1, 2], The composition of a dynamic combinatorial library (DCL) is thermodynamically driven and, as such, is able to adapt itself to any parameter that - permanently or transiently - modifies its constitution/energy potential surface [3,4], Thus, in the presence of various internal or external parameters, the involved equilibria can be displaced toward the amplification of given products through an adaptation process that will occur through an in situ screening of these species. A schematic representation using Emil Fisher lock-and-key metaphora can be used to illustrate these concepts (Fig. 1). 

Keywords Dynamic combinatorial library Constitutional dynamic chemistry Reversible reactions Supramolecular chemistry Thermodynamic control... 

A templated process can be driven thermodynamically or kinetically [23]. In the former case, the template binds more strongly to one of the products present in an equUibriiun (i.e., a mixture imder thermodynamic control) shifting the reaction towards the formation of this specific product which is then obtained in higher yields. As will be discussed later in this review, this is particularly important in the generation of dynamic combinatorial libraries. On the other hand, kinetic templates operate under irreversible conditions by stabilising the transition state leading to the final product. 

Fig. 2 Efficient syntheses of macrocycles for concave reagents using thermodynamic control for macrocyclizations (a) Formation of concave 1,10-phenanthrolines 2 by ring-closing metathesis (b) selection of niacrocyclic diimines 7 from a dynamic combinatorial library with the help of transition metal ions as templates and subsequent reduction to 8. here formation of an 18-membered macrocycle by using Ca. ...

This rationale led Severin et alP to construct an array consisting of CuCh, NiCh, and three UV-active chro-mophores, resulting in six metal-indicator combinations to comprise a dynamic combinatorial library. A dynamic combinatorial library is an array of differential sensors that are simultaneously present in one solution, under thermodynamic control, such that this one solution can provide multiple signals from the composite interactions of an analyte with all the sensors in solution. They found that this simple dynamic combinatorial library of receptors was able to successfully discriminate two angiotensin peptides (angiotensin I and angiotensin II) and mixtures of these two peptides. 

Dynamic combinatorial chemistry (DCC) has proven extremely useful in creating complex mixtures of interchanging compounds termed dynamic combinatorial libraries (DCL). Key to the formation of such DCLs is a reversible chemical process that allows the library members to interconvert. The formation of imines from aldehydes and amines is a prominent example for the creation of a DCL. Since the overall distribution of compounds is under thermodynamic control, external stimuli can be used to bias the DCL toward a specific member of the library. This approach has been exploited successfully in the search of potent receptors for molecules of pharmacological interest, the creation of supramolecular assemblies, and ligands for biomacromolecules. ... 

In this work, they describe a general approach for the synergistic relationships that exist at two length scales within a self-replicating dynamic combinatorial library. They show that molecnlar constituents can compete at the subnanometer scale for the reversible production of amphiphiUc dynamic block copolymers or surfactants (i.e., dynablocks, which are defined as species combining a hydrophobic and a hydrophilic moiety linked together by a reversible connection). The packing parameters of the condensed dynablocks determine the formation and the thermodynamic stability of... 

Dynamic combinatorial library A pool of constituents made of chemical species reversibly interconverting through either covalent or intermolecular interactions, with the actual composition of the library dependent on the relative thermodynamic stability of the library members. 

Dynamic combinatorial chemistry, as a method for the generation of new molecules by means of reversible reactions between simple building blocks under thermodynamic control. In a dynamic combinatorial library (DCL), all constituents are in equihbrium, and their distribution is determined by their... 

Fig. 6 Dynamic combinatorial peptide library that expioits enzyme reactions to control self-assembly processes under thermodynamic controi. (a) Emergence of the potentiai peptide derivatives of varying length in a library of interconverting molecules formed from the staring materials of Fmoc L/L2 system. Fmoc-Ls is preferentially formed. Corresponding AFM images of the fibrillar structures formed at 5 min after the addition of enzyme, and the sheet-like structures observed after 2000 h show that redistribution of the derivatives is accompanied by the remodelling from fibres (Fmoc L3) to sheet-like structures (Fmoc L5). (b) HPLC analysis of the composition of the system reveals the formation and the stabilisation of Fmoc-Ls over time. Modified from [21]...

---