Calix[4]pyrrole-based receptors for biologically relevant polar molecules: from organic to aqueous media
- Autores: Daniel Hernández Alonso
- Directores de la Tesis: Pablo Jose Ballester Balaguer (dir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: María Victoria Martínez Díaz (presid.), Pascal Blondeau (secret.), Francisco Najera Albendin (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencia y Tecnología Química por la Universidad Rovira i Virgili
- Materias:
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- Resumen
In summary, the work presented in this thesis describes the synthesis and binding studies of novel receptors based on aryl-extended calix[4]pyrrole macrocycles for the recognition of biologically relevant molecules.
After a brief introduction about water-soluble synthetic receptors able to form complexes with neutral organic guests in aqueous media through the establishment of hydrogen-bond interactions, we describe the synthesis of a novel water-soluble tetraphenyl-extended calix[4]pyrrole. In contrast to the previously described examples, the carboxylic water-solubilizing groups installed are distal to the polar aromatic binding site. This strategy leaves the aromatic binding site and the upper rim of the receptor intact, and allows a later functionalization of the meso-aryl rings, thus, permitting the construction of more elaborated water soluble calix[4]pyrroles. We demonstrated that the receptor forms thermodynamically and kinetically stable complexes with a series of pyridine N-oxide guests in aqueous solution. The binding geometry of these complexes was probed using 1H NMR titrations and their thermodynamic features were determined using ITC experiments. The anionic receptor described is able to bind negatively charged pyridine N-oxides (i.e. bearing a carboxylate moiety) with high affinity. The obtained results also demonstrated that in water the pyrrolic core of the receptor preferentially establishes hydrogen bonding interactions with the N-oxide moiety. Our results highlight the ability of the receptor’s aromatic pocket to protect the pyrrole N-H groups and ensure selective hydrogen-bonding interactions even in water solution.
In a following chapter, we describe the synthesis of an unprecedented monophosphonate bridged receptor capable of establishing a three-dimensional array of intermolecular interactions with neutral creatinine (Cr) and the creatininium cation (CrH+). The receptor forms thermodynamically stable inclusion complexes with a 1:1 stoichiometry in the case of neutral Cr. On the other hand, titration experiments with CrH+ showed the formation of two different aggregates having 1:1 and 2:1 stoichiometry. The use of a reference receptor, bis(methylene)-bridged derivative allowed us to assess the importance and the magnitude of the additional hydrogen-bonding interaction that is established between the inwardly directed polar phosphonate group and the NH2 unit of the included guest.
Combining our results described in the firsts chapters of the thesis, we next describe the synthesis of two unprecedented diastereoisomeric water-soluble bis-phosphonate calix[4]pyrrole cavitands 4dio and 4doo. The water solubilizing groups were also installed at the ends of the meso-alkyl substituents far away from the deep polar aromatic binding pocket. We assessed the binding constants of the two diastereoisomeric bis-phosphonate cavitands, 4dio and 4doo, with natural creatinine and with a lipophilic synthetic version containing a hexyl chain (HxCr) in water. Both receptors formed thermodynamically stable complexes featuring 1:1 stoichiometry. Surprisingly to us, the 4doo receptor showed higher binding affinities towards both guests. Remarkably, the presence of a phosphonate group inwardly directed towards the aromatic cavity in the 4dio isomer that can be involved in an extra hydrogen-bonding interaction with the included guest did not provide any additional energetically stabilization for the host:guest complex. We attributed these results to a more energetically demanding desolvation process for cavity entrance in the 4dio compared to the 4doo counterpart. Finally, we report that the 4doo isomer can also act as an effective receptor for diethyl nitrosamine (NDEA), a potent carcinogenic agent, in water. The complexation process is mainly driven by hydrogen-bonding interactions established between the oxygen atom of the N-nitroso moiety group and the pyrrole NHs of the receptor. To the best of our knowledge, these findings represent the first example of a synthetic receptor for NDEA.
Finally, the present thesis also collects the work related to on the synthesis of a fluorescent receptor based on an aryl-extended calix[4]pyrrole cavitand. Our receptor possesses a single phosphonate group, which not only acts as a bridging unit rigidifying the cavity, but also participates in the recognition process of creatinine through the establishment of hydrogen-bond interactions with the guest. The new described receptor possesses a strong emission band with a maxima at 501 nm attributed to the presence of the covalently connected dansyl group. We designed a fluorescent responsive supramolecular self-assembly based on two units of the fluorescent receptor bound by a ditopic guest (4,4’ dipyridyl N,N’-dioxide (DPNO)) to be further used for creatinine sensing. The supramolecular assembly was studied by 1H NMR, absorption and emission spectroscopy. The dimeric self-assembly experiences a self-quenching of the dansyl units fluorescence due to the close proximity of the fluorescent groups. Addition of a creatinine derivative, HxCr, provoked the disassembly of the aggregate with the consequent recovery of the fluorescence emission. In all processes, the fluorescence emission had a good linear fit with the concentration of HxCr and the estimated LOD resulted to be as low as 1.6 µM
