Receptores de aniões baseados em azacalix[4]arenos e isoftalamidas


In this thesis, developed within the PhD Program in Chemistry of the University of Aveiro, new synthetic receptors containing the macrocyclic platform tetraazacalix[2]arene[2]triazine or the isophthalamide scaffold were synthesized. Both structural units contain amide and urea as binding units for pharmacologically or biologically relevant anions, such as acetate, oxalate, malonate, succinate, glutarate, diglycolate, L- and D-alanine, (S)- and (R)-phenylpropanoate, (S,S)- and (R,R)-tartarate, fumarate, maleate, Cl-, HCO3-, H2PO4-, HSO4- and SO42-. Chapter 1 is dedicated to the state of art in the synthesis, structural characterization and applications of functional receptors related with the synthetic molecules developed within the scope of this thesis, with special attention to the ones that have been studied as anion receptors. While isophthalamides have been quite exploited in the anion recognition chemistry throughout the last 20 years, receptors inspired in the azacalix[2]arene[2]triazine moiety are still giving their first steps. In Chapter 2 is presented the synthesis of four new azacalix[2]arene[2]triazines bearing one or two L-alanine (A1, A2) or L-leucine (L1, L2) arms based in amide groups as recognition units, which are attached to the macrocyclic benzyl rings. Two other azacalix[2]arene[2]triazines containing one (U1) or two (U2) arms bearing urea groups, previously prepared by coupling (S)-methylbenzyl isocyanate and ethanolamine, are also presented. The bridging NH groups of azacalixarenes A2 and U2 were subsequently methylated, yielding A2Me4 and U2Me4. Only the anion affinity of these two molecules was investigated. The synthesized compounds were characterized through spectroscopic techniques, complemented by single crystal X ray diffraction in the case of U2Me4. The 3rd Chapter comprises the molecular recognition studies between both macrocycles A2Me4 and U2Me4 and the anions derived from mono- and dicarboxylic aliphatic acids, isomeric carboxylic acids (enantiomers and geometrical isomers), amino acids and also polioxanions, except for HCO3-. These studies were carried out through 1H NMR titration techniques with determination of their binding constants. All associations presented a 1:1 receptor-substrate stoichiometry except for the ones between A2Me4 and U2Me4 with H2PO4- (1:2). It was determined that the most stable complexes were A2Me4∙SO42- and U2Me4∙(H2PO4-)2, with stability constants of 7,4 × 104 M-1 and higher than 105 M-2, respectively. The recognition of the aliphatic dicarboxylates occurred through both arms of the macrocycle, with the carboxylate groups separated by the longest aliphatic chains (glutarate and diglycolate) yielding the best fine-tuned associations. No enantiosselective recognition was observed with the studied chiral anions. In contrast, the affinity constants for the associations with both the cis (maleate) and trans (fumarate) anionic isomers of but-2-enedioic acid, of 89 and 4920 M-1 for A2Me4 and 481 and 4007 M-1 for U2Me4, respectively, suggest that both receptors show selectivity towards fumarate. In Chapter 4 is described the synthesis of nine new acyclic isophthalamide receptors (Iso-1 – Iso-9) bearing lateral arms with anion recognition groups. While Iso-1 has recognition units based only on amide groups, Iso-2, Iso-3, Iso-5, Iso-6, Iso-7 and Iso-9 have both amide and urea units, and Iso-4 and Iso-8 have amide and sulfonylurea as binding units. All of these compounds contain a flexible ethylene spacer between the recognition groups of each arm, thus furnishing fine-tuned adjustments with the anions. The synthesized isophthalamide derivatives were characterized by spectroscopic techniques. Chapter 5 covers the 1H NMR association studies carried out between Iso-1, Iso-2, Iso-4, Iso-6 and Iso-8 with Cl-, H2PO4-, HCO3- and oxalate anions. Iso-1, Iso-2 and Iso-6 formed the strongest associations with oxalate, with association constants (Kass) of 6100, 7800 and 9800 M-1, respectively, and the weakest with Cl- (17 < Kass < 19 M-1). H2PO4- always formed stronger associations (294 < Kass < 427 M-1) than HCO3-, with the latter assembling preferably with Iso-2 (Kass = 95 M-1). The sulfonylurea groups of Iso-4 and Iso-8 were deprotonated in the presence of all anions, apart from Cl-. In Chapter 6, the main conclusions from this PhD research program are presented, and, at last, Chapter 7 describes all experimental procedures as well as the spectroscopic data of the synthesized compounds.

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Miguel Maurício Machado dos Santos

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Vítor Félix


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