Molecular recognition is a research area embedded within the field of Supramolecular Chemistry. The investigated model systems and the results derived from them are key for the understanding and mimicking of proteins’ binding affinity, selectivity and catalytic performances. In this regard, natural receptors bind efficiently polar substrates in water. Their binding pockets are hydrophobic clefts or cavities containing hydrophilic groups, which are shielded from water solvation. On the other hand, most synthetic receptors possess hydrophobic cavities deprived of polar binding groups. The incorporation of polar functions in the interior of non-polar cavities is synthetically challenge and hence, hydrophilic receptors are scarce in literature.
This Thesis deals with the design and synthesis of molecular containers featuring three-dimensional hydrophilic cavities. For their construction, we selected the aryl-extended calixpyrrole scaffold, which delivers a deep aromatic cavity closed at one end by a polar binding site and opened at the opposite end. The polar binding site comprises four pyrrole NHs. We prepared covalent receptors, self-assembled metallo-cages and non-covalent capsules. We investigated their molecular recognition properties in both organic solvents and water. The host-guest complexes were characterized thermodynamically and kinetically by NMR, ITC and UV/Vis methods. The understanding of the formation/dissociation processes of host-guest complexes, as well as the intermolecular forces involved, should provide valuable knowledge for the design of novel receptors with tuned functions.
Specifically, we describe the elongation of the cavity of aryl-extended calixpyrroles (AE-CP) affording super aryl-extended derivatives (SAE-CP). First, we studied the interaction of a tetra-ester SAE-CP with a series of N-oxides in chloroform solution. The SAE-CP receptor formed thermodynamically and kinetically highly stable 1:1 inclusion complexes featuring binding constant values larger than 10^6 M^-1. The results demonstrated the superior binding properties of the SAE-CP versus the parent AE-CP. The hydrolysis of the tetra-ester SAE-CP afforded the corresponding tetra-acid. Nevertheless, the tetra-acid SAE-CP was not soluble in water, suggesting the necessary incorporation of a larger number of ionizable or charged groups in the SAE-CP scaffold.
Next, we synthesized SAE-CPs bearing eight ionizable or charged groups. These SAE-CPs were soluble in neutral or basic water. We assessed the binding constants for the complexation of a series of pyridyl N-oxides, having different non-polar residues at their para-position, with the water-soluble receptors. The constant values were larger than 10^5 M^-1. Interestingly, we observed a linear relationship between the free energies of binding and the surface area of the non-polar residues. This allowed the quantification of the hydrophobic effect operating in these SAE-CP complexes. Furthermore, we show that a tetra-phenyl calixpyrrole receptor displays conformational selectivity for the binding of the cis-isomer of amides in water. This finding demonstrated that the AE-CP receptor functions as a minimal chaperone analogue.
We were also interested in designing molecular containers with a more pre-organized and enclosed cavity based on the SAE-CP scaffold. For their preparation, we followed two approaches: 1) sealing of the open end of the SAE-CP by metal coordination, and 2) self-assembly of SAE-CPs into non-covalent dimeric capsules. We demonstrated that a tetra-pyridyl SAE-CP ligand self-assembles into a mono-metallic Pd(II)/Pt(II)-cage featuring two different polar binding sites. We studied the (co)inclusion of sizable polar guests in the cage’s cavity. Based on the kinetic characterization of the cage complexes, we proposed viable mechanisms for the guest inclusion/exchange processes. The nature of the metal-ligand coordination bonds used for the cage assembly govern the available guest inclusion/exchange mechanism and the binding selectivity exhibited by these metallo-cages. Finally, we report the initial studies of the self-assembly of a tetra-urea SAE-CP into hydrogen-bonded dimeric capsules using pyridyl N-oxides as guests template.