Molecular recognition, metal coordination and self-assembly with macrocyclic receptors and multidentate pyridine ligands

Abstract

Supramolecular chemistry was defined for the first time by J. M. Lehn as “the chemistry beyond molecules” and studies molecular assemblies driven by non-covalent interactions. Supramolecular systems assemble by spontaneous thermodynamically-driven processes. Molecular recognition, self-assembly and metal coordination are common strategies to achieve sophisticated architectures. Being based on non-covalent interactions, supramolecular systems are reversible, and changes can often be triggered by external stimuli. For these reasons, supramolecular chemistry is an extremely active and fast developing field that finds applications from life sciences to smart materials. In this thesis, I report three case studies that involve the synthesis of supramolecular building blocks and the study of their assemblies. In the first case study, I showed the synthesis and study of multidentate pyridine ligands. Such ligands possessed a planar V-shaped scaffold comprising a pyridyl-acetylene system. Properties of the ligand could be tuned by functionalization. Solid state assemblies of the ligand were driven by H-bond, CH-N and CH-π interactions. Functional groups and solvent appeared to play a crucial role in the final packing. Furthermore, co-crystallization experiments with the halogen bond donor 1,4-diiodotetrafluorobenzene led to intricated architectures. The assembly, driven by X-bond, was again influenced by functional groups on the scaffold. Bromine substituents promoted porous assemblies, via Br-Br weak interactions. In addition, functionalization with carboxylic-acid moieties yielded to excellent ligands for metal coordination. I exploited such pyridine-carboxylic ligands to develop coordination polymers (CPs) via mechanochemical synthesis. Mechanochemical reactions exploit the energy gained from grinding of reagents together. Grinding has the advantages of employing low energies to obtain crystalline products in short reaction times (in the order of minutes) with quantitative yields. Very low amounts of solvent are required, making grinding a truly environmental-friendly technique. CPs are generally not soluble, hampering characterization through most common techniques. Thanks to the collaboration with Prof. Lara Righi (Department SCVSA, University of Parma), Dr. Mauro Gemmi (Italian Institute of Technology, Pisa) and his team, we characterized the materials with electron diffraction tomography. Electron diffraction is gaining increasing attention in crystallography as a technique to obtain structural information when single crystal XRD is not feasible. To our knowledge, mechanochemistry and electron diffraction have never been coupled to synthesize and characterize CPs. Our methodology is truly innovative in this recent developing field. The second case study concerned the preparation of functionalized cavitands as ligands for metal coordination. Coordination complexes based on macrocycles, have been widely studied and found application in many fields, including mimic biological systems, catalysis, molecular machines and gas adsorption and storage. In this study, I employed tetra-phosphonate cavitands, which provide interesting guest recognition properties. Tetra-phosphonate cavitands are bowl-shaped macrocycles constructed on a resorcin[4]arene scaffold. Resorcinarene hydroxyls are bridged with phosphonate groups pointing inward the cavity. The P=O groups provide an anchoring point for H-bond, dipole-dipole and cation-dipole interactions. I functionalized tetra-phosphonate cavitands with moieties suitable for metal coordination, leaving the P=O groups free for further guest complexation. The ligands synthesized have been studied from two different points of view. Initially we aimed at creating a capsule suitable for guest complexation. Our second goal was the study of 3D assembly of these complexes and the development of a framework or coordination polymer. During this process, I collected many structural data on coordination complexes of tetra-phosphonate cavitands with several metals. Remarkably, the lanthanum complex showed solvent-mediated dimerization. The assembly could be controlled by solvent exchange. Complexes were characterized in solution through NMR techniques, in particular DOSY NMR, and at the solid state through X-ray crystallography. In the third case has been carried out in the laboratory of Prof. P.B. Crowley (National Univeristy of Ireland Galway, Ireland). In this work, I reported molecular recognition between a model protein bearing dimethylated lysines and three synthetic receptors: tetra-phosphonate cavitand, p-sulfonatocalix[4]arene and cucurbit[7]uril. Proteins are governed by several post translational modifications, namely chemical alterations, of exposed residues. Mono-, di- and tri-methylation of the lysine ammonium (Nζ) are common post translational modifications that occur most notably in histones, with vast ramifications for gene expression. Methylated lysines (LysMen) present a unique hotspot for recognition by reader proteins that possess an aromatic cage motif. Consequently, synthetic receptors that recognize LysMen hold great potential as probes to study the biological systems and as inhibitors of protein-protein interactions. Supramolecular macrocycles are increasingly popular as receptors for protein binding and assembly and present an orthogonal strategy to peptide-based methods. To our knowledge, tetra-phosphonate cavitands recognition properties have never been tested on a model protein. Here, I demonstrated binding to a dimethylated model protein in solution. Binding constants were in the millimolar range. Anionic calixarenes have proven particularly useful for the assembly of cationic proteins. Here, I have discussed recognition and assembly mediated by p-sulfonatocalix[4]arene of a dimethylated neutral protein. A wide binding area was identified, both in solution and at the solid state. The calixarene mediated protein-protein interfaces, suggesting a strategy for impeding binding sites. Cucurbit[7]uril binds lysine with increasing affinity as the degree of methylation increases. Here, I reported the first structural characterization of host-guest complexation between cucurbit[7]uril and LysMe2 in a model protein. Binding was dominated by complete encapsulation of the dimethylammonium group. While selectivity for the most sterically accessible LysMe2 was observed both in solution and in the solid state, three different modes of complexation were revealed by X-ray crystallography. The crystal structures revealed also entrapped water molecules that solvated the ammonium group within the cucurbit[7]uril cavity. Remarkable protein assemblies, including inter-locked octahedral cages that comprise 24 protein trimers, occurred in the solid state. Cucurbituril clusters appear to be responsible for these assemblies, suggesting a strategy to control protein assembly. The three case studies report outstanding examples of molecular recognition, metal coordination and self-assembly, broadening the library of supramolecular systems.