My PhD studies have been focused on the synthesis and development of new supramolecular systems whose applications range from host molecules towards neutral and charged guest molecules, and building blocks for the construction of supramolecular polymers. The first system that hereby describes is the tetraammonium-oxacalix[4]arene 66·4HCl. This macrocycle, the first water-soluble member of its class, acts as 'molecular tweezers': despite being positively charged, when in the right protonation state it is able to overcome unfavourable repulsive effects and recognize and bind the dicationic guest, methyl viologen, in water. Binding takes place in the π-rich cleft generated by the two facing resorcinol rings, despite the electrostatic repulsion between the positive charges on the macrocycle and those on the guest. In-depth NMR, UV-Vis and DFT studies allowed us to measure the four protonation constants of 66 and demonstrate that only the tricationic form is able to positively interact (at an acidic pH) with the guest with a Ka = 253 ± 50 M–1. As a follow-up, we decided to test the versatility of this polycationic receptor towards a number of very different potential substrates. After several attempts, turned out that 2,7-dihydroxynaphtalene (DHN) is also recognized by our ionisable macrocycle. NMR coupled to semi-empirical calculations showed that, similarly the case of paraquat, the π-rich DHN guest nestles within the aromatic cleft generated by the resorcinol rings. In addition, it came out (again) that only the triprotonated form of the macrocycle (66·3H+) is able to significantly recognize the guest, albeit now with a modest Ka of 44 ± 4 M–1. Interesting structural data were provided by the computational studies. Optimisation of the geometry of the receptor – with its three chloride counterions – and of the guest within a cluster of 200 explicit solvent molecules (H2O) showed that the guest lies within the cavity of the receptor, with its hydroxyl groups pointing away from the oxacalixarene cavity, in order to hydrogen-bond with the surrounding solvating water molecules. These findings suggested that π-staking interactions are not the only driving force of this complexation event, but rather that the solvent plays a crucial role through hydrophobic and solvent effects. Encouraged by the results obtained with the tetraamino-derivative 66, and aware that solubility somehow limited its general applicability, we turned our attention to compounds such as [4,6,16,18]tetra-amino[11,23]dihydroxy-tetraoxacalix[4]arene 68·2H and [4,6,16,18]tetra-amino[25,27]dihydroxy-tetraoxacalix[4]arene 70·2H. The introduction of two additional ionisable exo- or endo-cyclic phenolic groups on the oxacalixarene skeleton led to an increased water solubility. We undertook a comparative (with respect to 66) paraquat binding study with compound 70∙2H. Remarkably, the greater stability throughout the pH range of the new receptor − due to the introduction of the two additional (de)protonable sites (i.e., the OH groups) − allowed us to investigate host-guest association also at basic pH values, a range that remained unexplored in our previous study, given the limited solubility of 1∙nH+ at pH > 2.5. The apparent association constants for the 70∙nH(n–2)+PQT2+ complex at low pH proceeds with a similar efficiency to that seen above for 66∙nHn+PQT2+. Moreover, at basic pH, when oxacalixarene becomes negatively charged the stability of the 70∙nH(n–4)–PQT2+ (n = 5,6) complexes is higher than in acidic media, as a consequence of additional electrostatic attractive interactions (e.g., Kapp = 700 M–1 at pH 11.59). Within the same frame, we also synthesised two molecular cages, 75 and 77, with the goal of using them as cryptand-like receptors. Compounds 75 and 77 where characterized by 1H and DOSY NMR techniques, whereas semiempirical calculations suggested that, while 75 does not appear to posses a well-defined cavity, cage 77 presents a roughly spherical inner space, that may potentially accommodate small guest molecules. Where the first part of my work was devoted to 'basic' (i.e., amino-bearing) macrocycles, the second part dealt with 'acidic' (i.e., carboxyl-bearing) ones. Our research group has focused, for several years, on the development of new supramolecular systems based on classical calix[5]arene building blocks. Within this frame, we recently focused on a solid state investigation on the recognition properties of tetraester-calix[5]arene carboxylic acid 98·H, which was found to be able to form capsular or quasi-capsular complexes with , diaminoalkanes (H2N[CH2]nNH2) as their ammonium dications, generated after a double host-to-guest proton transfer event. The solid state structure of the 98−H3N(CH2)10NH3+98− and 98−+H3N(CH2)11NH3+98− complexes reveals that the proton-transfer-mediated encapsulation has taken place, and that the diprotonated guest is nestled within the confined space defined by two calix[5]arene units. The guest adopts a fully extended zigzag conformation, spanning the space between the bottoms of the receptor cavities, whereas the calixarenes adopt a cone-out conformation, mandatory for ammonium endo-cavity inclusion. The complex is held together by a number of concomitant interactions: the hydrogen bonds between ammonium ions and three oxygen atoms belonging to three different phenolic rings and an ester carbonyl oxygen atom, CH-π interactions between the  and -CH2 groups at the two ends of the ammonium guest and the calixarene aromatic rings. In addition, the wider rim tert-butyl moieties are in van der Waals contact providing, at the same time, sealing of the endo-capsular space and additional weak attractive interactions. The solid state structure of 98−+H3N(CH2)12NH3+98− showed many differences with respect to the other two systems, due to the longest guest chain that fails to fit within a capsule formed by two calix[5]arene units. Although +H3N(CH2)12NH3+ adopts a single highly compressed conformation, the two calixarene molecules do not come into van der Waals contact, giving rise to a quasi-capsular assembly. Willing to test the efficiency of our capsule design beyond the proof-of-concept stage, we decided to move forward and pit calix[5]arene carboxylic acid 99·H against potential guests with a mismatched number of protonable sites. To this end, the biogenic polyamines, spermine (Spm) and norspermine (Nspm), were selected as tetraamino-containing guests. Contrary to the low affinity seen in solution, solid-state structure analyses of the two complexes revealed an altogether different picture. The structure of the norspermine capsular complex (99–Nspm·2H+99–), shows that encapsulation of the dicationic form of the guest –within two facing carboxylate-calix[5]arene cavities – takes place as a result of an initial acid-base host-to-guest proton transfer. The two calix[5]arene molecules, as generally seen in the case of alkylammonium endo-cavity inclusion complexes in the solid state, are arranged in a typical (approximately CS-symmetric) cone-out conformation. A similar picture is seen for the solid-state structure of the spermine capsular complex (99–Spm·2H+99–). Again, regioselective acid-base proton-transfer generates a three-component salt-bridged supramolecular complex very similar to the one just described. This recognition motif was harnessed for the self-assembly of internally-ion-paired AABB-type supramolecular polymers. DOSY NMR investigations reveal that bis-calix[5]arene-bis-carboxylic acids 106∙2H–108∙2H, upon exposure to ,-diaminoalkanes self-assemble by iterative proton-transfer-mediated recognition, ultimately producing overall neutral aggregates. DLS and AFM allowed to discover that 108∙2H, when mixed with 1,12-diaminododecane gives cyclic oligomeric assemblies, whose morphology (i.e., cyclic vs. linear) can be controlled by means of external chemical stimuli. A further macrocycle investigated during my PhD is based on a dithia[3.3]paracyclophane framework, attractive materials that can be used as comonomers in the preparation of a wide range of π-conjugated copolymers. The synthesis of some of these derivatives proceeds with complete stereoselection, resulting in the exclusive formation of the meso-diastereoisomers. We undertook a theoretical study on the mechanism underlying the formation of dithia[3.3]paracyclophane S,S'-dioxide (R,S)-125 and a density functional study on the transition state of the cyclisation was carried out, to examine the pathways that could lead to (R,S)-125 or to the diastereomeric racemic mixture (R,R)/(S,S)-125 discovering that the exclusive formation of the meso-(S,R)-125 proceeds under kinetic control.

The supramolecular chemistry of ionisable (oxa)calixarenes

MANGANARO, NADIA
2017-02-15

Abstract

My PhD studies have been focused on the synthesis and development of new supramolecular systems whose applications range from host molecules towards neutral and charged guest molecules, and building blocks for the construction of supramolecular polymers. The first system that hereby describes is the tetraammonium-oxacalix[4]arene 66·4HCl. This macrocycle, the first water-soluble member of its class, acts as 'molecular tweezers': despite being positively charged, when in the right protonation state it is able to overcome unfavourable repulsive effects and recognize and bind the dicationic guest, methyl viologen, in water. Binding takes place in the π-rich cleft generated by the two facing resorcinol rings, despite the electrostatic repulsion between the positive charges on the macrocycle and those on the guest. In-depth NMR, UV-Vis and DFT studies allowed us to measure the four protonation constants of 66 and demonstrate that only the tricationic form is able to positively interact (at an acidic pH) with the guest with a Ka = 253 ± 50 M–1. As a follow-up, we decided to test the versatility of this polycationic receptor towards a number of very different potential substrates. After several attempts, turned out that 2,7-dihydroxynaphtalene (DHN) is also recognized by our ionisable macrocycle. NMR coupled to semi-empirical calculations showed that, similarly the case of paraquat, the π-rich DHN guest nestles within the aromatic cleft generated by the resorcinol rings. In addition, it came out (again) that only the triprotonated form of the macrocycle (66·3H+) is able to significantly recognize the guest, albeit now with a modest Ka of 44 ± 4 M–1. Interesting structural data were provided by the computational studies. Optimisation of the geometry of the receptor – with its three chloride counterions – and of the guest within a cluster of 200 explicit solvent molecules (H2O) showed that the guest lies within the cavity of the receptor, with its hydroxyl groups pointing away from the oxacalixarene cavity, in order to hydrogen-bond with the surrounding solvating water molecules. These findings suggested that π-staking interactions are not the only driving force of this complexation event, but rather that the solvent plays a crucial role through hydrophobic and solvent effects. Encouraged by the results obtained with the tetraamino-derivative 66, and aware that solubility somehow limited its general applicability, we turned our attention to compounds such as [4,6,16,18]tetra-amino[11,23]dihydroxy-tetraoxacalix[4]arene 68·2H and [4,6,16,18]tetra-amino[25,27]dihydroxy-tetraoxacalix[4]arene 70·2H. The introduction of two additional ionisable exo- or endo-cyclic phenolic groups on the oxacalixarene skeleton led to an increased water solubility. We undertook a comparative (with respect to 66) paraquat binding study with compound 70∙2H. Remarkably, the greater stability throughout the pH range of the new receptor − due to the introduction of the two additional (de)protonable sites (i.e., the OH groups) − allowed us to investigate host-guest association also at basic pH values, a range that remained unexplored in our previous study, given the limited solubility of 1∙nH+ at pH > 2.5. The apparent association constants for the 70∙nH(n–2)+PQT2+ complex at low pH proceeds with a similar efficiency to that seen above for 66∙nHn+PQT2+. Moreover, at basic pH, when oxacalixarene becomes negatively charged the stability of the 70∙nH(n–4)–PQT2+ (n = 5,6) complexes is higher than in acidic media, as a consequence of additional electrostatic attractive interactions (e.g., Kapp = 700 M–1 at pH 11.59). Within the same frame, we also synthesised two molecular cages, 75 and 77, with the goal of using them as cryptand-like receptors. Compounds 75 and 77 where characterized by 1H and DOSY NMR techniques, whereas semiempirical calculations suggested that, while 75 does not appear to posses a well-defined cavity, cage 77 presents a roughly spherical inner space, that may potentially accommodate small guest molecules. Where the first part of my work was devoted to 'basic' (i.e., amino-bearing) macrocycles, the second part dealt with 'acidic' (i.e., carboxyl-bearing) ones. Our research group has focused, for several years, on the development of new supramolecular systems based on classical calix[5]arene building blocks. Within this frame, we recently focused on a solid state investigation on the recognition properties of tetraester-calix[5]arene carboxylic acid 98·H, which was found to be able to form capsular or quasi-capsular complexes with , diaminoalkanes (H2N[CH2]nNH2) as their ammonium dications, generated after a double host-to-guest proton transfer event. The solid state structure of the 98−H3N(CH2)10NH3+98− and 98−+H3N(CH2)11NH3+98− complexes reveals that the proton-transfer-mediated encapsulation has taken place, and that the diprotonated guest is nestled within the confined space defined by two calix[5]arene units. The guest adopts a fully extended zigzag conformation, spanning the space between the bottoms of the receptor cavities, whereas the calixarenes adopt a cone-out conformation, mandatory for ammonium endo-cavity inclusion. The complex is held together by a number of concomitant interactions: the hydrogen bonds between ammonium ions and three oxygen atoms belonging to three different phenolic rings and an ester carbonyl oxygen atom, CH-π interactions between the  and -CH2 groups at the two ends of the ammonium guest and the calixarene aromatic rings. In addition, the wider rim tert-butyl moieties are in van der Waals contact providing, at the same time, sealing of the endo-capsular space and additional weak attractive interactions. The solid state structure of 98−+H3N(CH2)12NH3+98− showed many differences with respect to the other two systems, due to the longest guest chain that fails to fit within a capsule formed by two calix[5]arene units. Although +H3N(CH2)12NH3+ adopts a single highly compressed conformation, the two calixarene molecules do not come into van der Waals contact, giving rise to a quasi-capsular assembly. Willing to test the efficiency of our capsule design beyond the proof-of-concept stage, we decided to move forward and pit calix[5]arene carboxylic acid 99·H against potential guests with a mismatched number of protonable sites. To this end, the biogenic polyamines, spermine (Spm) and norspermine (Nspm), were selected as tetraamino-containing guests. Contrary to the low affinity seen in solution, solid-state structure analyses of the two complexes revealed an altogether different picture. The structure of the norspermine capsular complex (99–Nspm·2H+99–), shows that encapsulation of the dicationic form of the guest –within two facing carboxylate-calix[5]arene cavities – takes place as a result of an initial acid-base host-to-guest proton transfer. The two calix[5]arene molecules, as generally seen in the case of alkylammonium endo-cavity inclusion complexes in the solid state, are arranged in a typical (approximately CS-symmetric) cone-out conformation. A similar picture is seen for the solid-state structure of the spermine capsular complex (99–Spm·2H+99–). Again, regioselective acid-base proton-transfer generates a three-component salt-bridged supramolecular complex very similar to the one just described. This recognition motif was harnessed for the self-assembly of internally-ion-paired AABB-type supramolecular polymers. DOSY NMR investigations reveal that bis-calix[5]arene-bis-carboxylic acids 106∙2H–108∙2H, upon exposure to ,-diaminoalkanes self-assemble by iterative proton-transfer-mediated recognition, ultimately producing overall neutral aggregates. DLS and AFM allowed to discover that 108∙2H, when mixed with 1,12-diaminododecane gives cyclic oligomeric assemblies, whose morphology (i.e., cyclic vs. linear) can be controlled by means of external chemical stimuli. A further macrocycle investigated during my PhD is based on a dithia[3.3]paracyclophane framework, attractive materials that can be used as comonomers in the preparation of a wide range of π-conjugated copolymers. The synthesis of some of these derivatives proceeds with complete stereoselection, resulting in the exclusive formation of the meso-diastereoisomers. We undertook a theoretical study on the mechanism underlying the formation of dithia[3.3]paracyclophane S,S'-dioxide (R,S)-125 and a density functional study on the transition state of the cyclisation was carried out, to examine the pathways that could lead to (R,S)-125 or to the diastereomeric racemic mixture (R,R)/(S,S)-125 discovering that the exclusive formation of the meso-(S,R)-125 proceeds under kinetic control.
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