Acid-base properties of cyclodextrins (CDs), persubstituted at C-6 by 3-mercaptopropionic acid, sualphadex (Suα-CD), subetadex (Suβ-CD) and sugammadex (Suγ-CD, the antidote of neuromuscular blocking steroids) were studied by ¹H NMR-pH titrations. For each CD, the severe overlap in protonation steps prevented the calculation of macroscopic pK_a values using the standard data fitting model. Considering the full symmetry of polycarboxylate structures, we reduced the number of unknown NMR parameters in the “Q-fitting” or the novel “equidistant macroscopic” evaluation approaches. These models already provided pK_a values, but some of them proved to be physically unrealistic, deceptively suggesting cooperativity in carboxylate protonations. The latter problem could be circumvented by adapting the microscopic site-binding (cluster expansion) model by Borkovec, which applies pairwise interactivity parameters to quantify the mutual basicity-decreasing effect of carboxylate protonations. Surprisingly, only a single averaged interactivity parameter could be calculated reliably besides the carboxylate ‘core’ microconstant for each CD derivative. The speciation of protonation isomers hence could not be resolved, but the optimized microscopic basicity parameters could be converted to the following sets of macroscopic pK_a values: 3.84, 4.35, 4.81, 5.31, 5.78, 6.28 for Suα-CD; 3.82, 4.31, 4.73, 5.18, 5.64, 6.06, 6.54 for Suβ-CD and 3.83, 4.28, 4.65, 5.03, 5.43, 5.81, 6.18, 6.64 for Suγ-CD. The pH-dependent charge of these compounds can now be accurately calculated, in support of designing new analytical methods to exploit their charge-dependent molecular recognition such as in cyclodextrin-aided chiral capillary electrophoresis.

In order to better understand the chiral recognition mechanisms of positively charged cyclodextrin (CD) derivatives, the synthesis, the pK_a determination by ¹H nuclear magnetic resonance (NMR)-pH titration and a comparative chiral capillary electrophoretic (CE) study were performed with two series of mono-substituted cationic single isomer CDs. The first series of selectors were mono-(6-N-pyrrolidine-6-deoxy)-β-CD (PYR-β-CD), mono-(6-N-piperidine-6-deoxy)-β-CD (PIP-β-CD), mono-(6-N-morpholine-6-deoxy)-β-CD (MO-β-CD) and mono-(6-N-piperazine-6-deoxy)-β-CD (PIPA-β-CD), carrying a pH-adjustable moiety at the narrower rim of the cavity, while the second set represented by their quaternarized, permanently cationic counterparts: mono-(6-N-(N-methyl-pyrrolidine)-6-deoxy)-β-CD (MePYR-β-CD), mono-(6-N-(N-methyl-piperidine)-6-deoxy)-β-CD (MePIP-β-CD), mono-(6-N-(N-methyl-morpholine)-6-deoxy)-β-CD (MeMO-β-CD) and mono-(6-N-(4,4-N,N-dimethyl-piperazine)-β-CD (diMePIPA-β-CD). Based on pH-dependent and selector concentration-dependent comparative studies of these single isomer N-heterocyclic CDs presented herein, it can be concluded that all CDs could successfully be applied as chiral selectors for the enantiodiscrimination of several negatively charged and zwitterionic model racemates. The substituent-dependent enantiomer migration order reversal of dansylated-valine using PIP-β-CD contrary to PYP-β-CD, MO-β-CD and PIPA-β-CD was also studied by ¹H- and 2D ROESY NMR experiments.

In the quest for new therapies targeting hypoxia, aromatic endoperoxides have intriguing potential as oxygen releasing agents (ORAs) able to free O₂ in tissues upon suitable trigger. Four aromatic substrates were synthesized and the formation of their corresponding endoperoxides was optimized in organic solvent upon selective irradiation of Methylene Blue, a low‐cost photocatalyst, producing the reactive singlet oxygen species. Complexation of the hydrophobic substrates within a hydrophilic cyclodextrin (CyD) polymer allowed their photooxygenation in homogeneous aqueous environment using the same optimized protocol upon dissolution in water of the three readily accessible reagents. Notably, reaction rates were comparable in buffered D₂O and organic solvent and, for the first time, the photooxygenation of highly hydrophobic substrates was achieved for millimolar solutions in non‐deuterated water. Quantitative conversion of the substrates, straightforward isolation of the endoperoxides and recovery of the polymeric matrix were achieved. Cycloreversion of one ORA to the original aromatic substrate was observed upon thermolysis. These results hold great potential for the launch of CyD polymers both as reaction vessels for green, homogeneous photocatalysis and as carrier for the delivery of ORAs in tissues.

Thiourea and structurally related urea derivatives are widely recognised for their ability to transport anions through hydrogen bonding interactions. The strength of these interactions correlates with the electronegativity of the ligand and the acidity of the NH hydrogens involved. Thiourea, being more acidic than urea, exhibits partial deprotonation in the presence of certain anions such as organic carboxylates, fluoride, and bromide, while remaining resistant to deprotonation by chloride. This behaviour suggests a degree of selectivity toward chloride ions. Additionally, while carbamide-containing molecules tend to aggregate—potentially reducing their ion-binding efficiency—thiourea derivatives show reduced aggregation, preserving their binding capabilities. In this study, we report the synthesis and characterisation of 21 novel thiourea derivatives obtained by reacting 2-aminobenzoylamino acid esters with various substituted phenyl isothiocyanates. Seven similar thiourea-containing molecules were made as a comparison—without the amino acids—by reacting aniline with the different phenyl isothiocyanates. The reaction kinetics were found to be influenced primarily by the electronic nature of the substituents on the phenyl ring. Electron-withdrawing groups (EWGs), such as para-nitro, 3,5-bis(trifluoromethyl), and fluorine, accelerated the reaction, while electron-donating groups (EDGs), such as para-methoxy, slowed it down. Interestingly, the nature of the amino acid precursors had no significant impact on reaction time; however, reactions with aniline proceeded the fastest. Solvent choice also played a role: reactions in N,N-dimethylformamide (DMF) proceeded faster than in acetone, although with reduced yields. Consequently, reaction conditions were optimised to balance time efficiency and product yield. To evaluate the chloride ion-binding properties of the synthesised compounds, ¹H NMR titration experiments were conducted in deuterated dimethyl sulfoxide (DMSO-d₆). The association constants (K_a) derived from these studies revealed a clear correlation with the electronic nature of the substituents. Compounds bearing EWGs exhibited enhanced chloride binding, while those with EDGs showed diminished binding affinity. Surprisingly, the presence of amino acid moieties led to a decrease in K_a values, despite the electron-withdrawing nature of the amide groups. This suggests that steric or conformational factors may play a role in modulating binding strength. Overall, the synthesised thiourea derivatives demonstrate mild, reversible chloride ion-binding behaviour, making them promising candidates for further development as selective anion receptors. The insights gained from this study contribute to a deeper understanding of structure–activity relationships in anion-binding systems and may inform the design of future supramolecular architectures with tailored ion recognition properties.