Final Report Summary - DYNACAT (Catalysis in Dynamic Molecular Networks) Most catalytic reactions in Nature are mediated by enzymes. The concentrations of these enzymes are controlled in space and time through elaborate regulatory mechanisms, giving rise to complex functional behaviour that is essential to biology. Synthetic catalysts have been developed, many of which complement enzymatic catalysis with respect to types of reactions and substrate scope. Yet, in synthetic systems, temporal control over catalyst concentrations remains underdeveloped, imposing limits on the functional potential. We reasoned that more elaborate control over synthetic catalysts may be achieved using a dynamic molecular network. Such networks have been mostly used for creating dynamic combinatorial libraries (DCLs), In dynamic combinatorial chemistry, a small set of building blocks react to form a combinatorial library of molecules that continuously exchange their building blocks, producing an equilibrium mixture.At the starting point of this project, there was one precedent in the group of a transient substrate-induced catalyst formation in a dynamic molecular network. An aza-Cope rearrangement rate was enhanced in the presence of a dynamic combinatorial library (DCL) formed from an aromatic dithiol building block (for achieving disulfide exchange) while, in turn, the presence of the reaction substrate induced the formation of its catalyst (a tetrameric macrocycle) from the DCL. This system’s conditions have been optimized to avoid the initial problems of aggregation of the catalyst.New bulkier reaction substrates have been designed to study whether they would give rise to the amplification of different macrocycles (with catalytic activity) from, otherwise, identical libraries. Their synthesis has been performed by a supervised student in a 3 week practical course. Although their isolation in pure form has not been achieved, the initial templating studies suggested that their behaviour in the studied system was identical to that of the initial substrate.New catalytic systems have been found for the discussed reaction. In an attempt to enhance the catalytic properties of the system, mixed libraries containing different building blocks (dithiols in all cases) have been studied. It was possible to find new systems which presented reaction rates comparable to that of the initial system, although the newly found reaction rate was not high enough so that it allowed for working towards the objective of controlling catalysis by added effector molecules, as we introduced in the grant proposal.Furthermore, the possibility of finding feedback behavior on these systems has been explored by trying to find DCLs that were responsive to the reaction products. Regretfully, no template effects were observed when adding the reaction products to the studied libraries.In an effort to try to obtain feedback behavior, other possible (structurally different) reaction products have been studied. Though some of them did indeed show intriguing templating effects on these mixed disulfide-based libraries, so far the synthesis of their corresponding aza-Cope substrate (performed in collaboration with a visiting PhD student) has proved unsuccessful.Trying to find new reactions that could be catalyzed by our systems, a 1,3-dipolar cycloaddition was studied. When trying to carry out the reaction intermolecularly, although a transition state analog (TSA; when a compound resembling the transition state of a chemical reaction is used as a template, any amplified library members are potential catalysts) showed promising templating properties in the studied libraries, the reaction did never proceed in the presence of the aforementioned libraries.On the other hand, a substrate for an intramolecular 1,3-dipolar cycloaddition was designed and synthesized. Again, the corresponding TSA showed interesting templating effects in some of the libraries. In this case, the reaction was accelerated with respect to the background process, though the reaction rate acceleration was modest even for the best results.Simultaneously to the main project, another one was continued in parallel. A new building block developed in the group (also a structurally simple aromatic dithiol) was studied because it produced surprisingly diverse libraries with the amplification of macrocycles of different size when different amines, polyamines and ammonium salts were used as templates. One of the produced macrocycles was isolated from a library (through preparative HPLC) and binding studies between the host and guest have been conducted using isothermal titration calorimetry (ITC). The synthesis of a structurally related building block (partially described in the literature, but for which a full study of its behaviour in water has never been carried out) has been performed by a supervised exchange PhD student. Its behaviour in DCLs has been studied, though it shows less variability on the formed macrocyles or its amplifications than the previous case.