Enhancing the Cation-Binding Ability of Fluorescent Calixarene Derivatives: Structural, Thermodynamic, and Computational Studies.

Novel fluorescent calix[4]arene derivatives L1 and L2 were synthesized by introducing phenanthridine moieties at the lower calixarene rim, whereby phenanthridine groups served as fluorescent probes and for cation coordination. To enhance the cation-binding ability of the ligands, besides phenanthridines, tertiary-amide or ester functionalities were also introduced in the cation-binding site. Complexation of the prepared compounds with alkali metal cations in acetonitrile (MeCN), methanol (MeOH), ethanol (EtOH), N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO) was investigated at 25 °C experimentally (UV spectrophotometry, fluorimetry, microcalorimetry, and in the solid state by X-ray crystallography) and by means of computational techniques (classical molecular dynamics and DFT calculations). The thermodynamic parameters (equilibrium constants and derived standard reaction Gibbs energies, reaction enthalpies, and entropies) of the corresponding reactions were determined. The tertiary-amide-based compound L1 was found to have a much higher affinity toward cations compared to ester derivative L2, whereby the stabilities of the ML1+ and ML2+ complexes were quite solvent-dependent. The stability decreased in the solvent order: MeCN ≫ EtOH > MeOH > DMF > DMSO, which could be explained by taking into account the differences in the solvation of the ligands as well as free and complexed alkali metal cations in the solvents used. The obtained thermodynamic quantities were thoroughly discussed regarding the structural characteristics of the studied compounds, as well as the solvation abilities of the solvents examined. Molecular and crystal structures of acetonitrile and water solvates of L1 and its sodium complex were determined by single-crystal X-ray diffraction. The results of computational studies provided additional insight into the L1 and L2 complexation properties and structures of the ligands and their cation complexes.

Elucidating mechanochemical reactivity of a ternary halogen-bonded cocrystal system by computational and calorimetric studies.

Discovery of a halogen-bonded ternary cocrystal of 1,3,5-trifluoro-2,4,6-triiodobenzene with pyrazine and triphenylphosphine sulfide has revealed a complex landscape of multicomponent phases, all achievable by mechanochemical interconversion. The observed solid-state reaction pathways were explained by periodic density-functional calculations and comprehensive intermolecular interaction analysis, supported by dissolution calorimetry measurements.

Utilization of a kinetic isotope effect to decrease decomposition of ceftriaxone in a mixture of D2O/H2O.

The discovery of cephalosporin and demonstration of its improved stability in aqueous solution, as well as enhanced in vitro activity against penicillin-resistant organisms, were major breakthroughs in the development of ß-lactam antibiotics. Although cephalosporins are more stable with respect to hydrolytic degradation than penicillins, they still experience a variety of chemical transformations. The present study offers an insight into the rates and mechanisms of ceftriaxone degradation at the therapeutic concentration in water, a mixture of water and deuterium oxide, and deuterium oxide itself at the neutral pH. Specific ceftriaxone degradation products were observed in aged samples (including a previously unreported dimer-type species), and by comparing the degradation rates in H2O and D2O, the observation of a kinetic isotope effect provided some valuable insight as to the nature of the initial ceftriaxone degradation. The effect of protium to deuterium isotope change on the degradation kinetics of ceftriaxone was evaluated using the method of initial rates based on HPLC analysis as well as by quantitative 1H NMR spectroscopy. Moreover, computational analysis was utilized to get a molecular insight into chemical processes governing the ceftriaxone degradation and to rationalize the stabilizing effect of replacing H2O with D2O.

Computational evaluation of halogen-bonded cocrystals enables prediction of their mechanochemical interconversion reactions.

Periodic density-functional theory (DFT) calculations were used to predict the thermodynamic stability and the likelihood of interconversion between a series of halogen-bonded cocrystals. The outcomes of mechanochemical transformations were in excellent agreement with the theoretical predictions, demonstrating the power of periodic DFT as a method for designing solid-state mechanochemical reactions prior to experimental work. Furthermore, the calculated DFT energies were compared with experimental dissolution calorimetry measurements, marking the first such benchmark for the accuracy of periodic DFT calculations in modelling transformations of halogen-bonded molecular crystals.

The Role of Triazole and Glucose Moieties in Alkali Metal Cation Complexation by Lower-Rim Tertiary-Amide Calix[4]arene Derivatives.

The binding of alkali metal cations with two tertiary-amide lower-rim calix[4]arenes was studied in methanol, N,N-dimethylformamide, and acetonitrile in order to explore the role of triazole and glucose functionalities in the coordination reactions. The standard thermodynamic complexation parameters were determined microcalorimetrically and spectrophotometrically. On the basis of receptor dissolution enthalpies and the literature data, the enthalpies for transfer of reactants and products between the solvents were calculated. The solvent inclusion within a calixarene hydrophobic basket was explored by means of 1H NMR spectroscopy. Classical molecular dynamics of the calixarene ligands and their complexes were carried out as well. The affinity of receptors for cations in methanol and N,N-dimethylformamide was quite similar, irrespective of whether they contained glucose subunits or not. This indicated that sugar moieties did not participate or influence the cation binding. All studied reactions were enthalpically controlled. The peak affinity of receptors for sodium cation was noticed in all complexation media. The complex stabilities were the highest in acetonitrile, followed by methanol and N,N-dimethylformamide. The solubilities of receptors were greatly affected by the presence of sugar subunits. The medium effect on the affinities of calixarene derivatives towards cations was thoroughly discussed regarding the structural properties and solvation abilities of the investigated solvents.

Solvophobically Driven Complexation of Adamantyl Mannoside with ß-Cyclodextrin in Water and Structured Organic Solvents.

Invited for the cover of this issue is Josip Pozar with collaborators from the University of Zagreb. The image depicts the differences in high- and low-temperature water effect on the complexation thermodynamics of adamantyl mannoside with ß-cyclodextrin. Read the full text of the article at 10.1002/chem.202000282.

Solvophobically Driven Complexation of Adamantyl Mannoside with ß-Cyclodextrin in Water and Structured Organic Solvents.

The effects of solvent and temperature on the complexation of adamantyl mannoside with ß-cyclodextrin and 6-O-monotosyl-6-deoxy-ß-cyclodextrin were explored experimentally and by means of molecular dynamics simulations. Efficient binding was observed only in hydrogen-bonded solvents, which indicated solvophobically driven complexation. The stability of the inclusion complex was considerably higher in aqueous media. A pronounced temperature dependence of Δr H○ and Δr S○ , resulting in perfect enthalpy-entropy compensation, was observed in water. The complexation thermodynamics was in line with classical rationale for the hydrophobic effect at lower temperatures and the nonclassical explanation at higher temperatures. This finding linked cyclodextrin complexation thermodynamics with insights regarding the effect of temperature on the hydration water structure. The complexation enthalpies and entropies were weakly dependent on temperature in organic media. The signs of Δr H○ and Δr S○ were in accordance with the nonclassical hydrophobic (solvophobic) effect. The structures of the optimized product corresponded to those deduced spectroscopically, and the calculated and experimentally obtained values of Δr G○ were in very good agreement. This investigation clearly demonstrated that solvophobically driven formation of cyclodextrin complexes could be anticipated in structured solvents in general. However, unlike in water, adamantane and the host cavity behaved solely as structure breakers in the organic media explored so far.

Functional self-assembled nanovesicles based on ß-cyclodextrin, liposomes and adamantyl guanidines as potential nonviral gene delivery vectors.

Multicomponent self-assembled supramolecular nanovesicles based on an amphiphilic derivative of ß-cyclodextrin and phosphatidylcholine liposomes (PC-liposomes) functionalized with four structurally different adamantyl guanidines were prepared and characterized. Incorporation efficiency of the examined adamantyl guanidines as well as size and surface charge of the prepared supramolecular nanovesicles was determined. Changes in the surface charge of the prepared nanovesicles confirmed that guanidinium groups were exposed on the surface. ITC and 1H NMR spectroscopy complemented by molecular dynamics (MD) simulations were used to elucidate the structural data and stability of the inclusion complexes of ß-cyclodextrin and adamantyl guanidines (AG1-5). The results are consistent and point to a significant contribution of the guanylhydrazone residue to the complexation process for AG1 and AG2 with ß-cyclodextrin. In order to evaluate the potential of the self-assembled supramolecular nanomaterial as a nonviral gene delivery vector, fluorescence correlation spectroscopy was used. It showed that the prepared nanovesicles functionalized with adamantyl guanidines AG1-4 effectively recognize and bind the fluorescently labelled DNA. Furthermore, gel electrophoretic assay confirmed the formation of nanoplexes of functionalized nanovesicles and plasmid DNA. These findings together suggest that the designed supramolecular nanovesicles could be successfully applied as nonviral gene delivery vectors.

Solvation Effect on Complexation of Alkali Metal Cations by a Calix[4]arene Ketone Derivative.

The medium effect on the complexation of alkali metal cations with a calix[4]arene ketone derivative (L) was systematically examined in methanol, ethanol, N-methylformamide, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. In all solvents the binding of Na+ cation by L was rather efficient, whereas the complexation of other alkali metal cations was observed only in methanol and acetonitrile. Complexation reactions were enthalpically controlled, while ligand dissolution was endothermic in all cases. A notable influence of the solvent on NaL+ complex stability could be mainly attributed to the differences in complexation entropies. The higher NaL+ stability in comparison to complexes with other alkali metal cations in acetonitrile was predominantly due to a more favorable complexation enthalpy. The 1H NMR investigations revealed a relatively low affinity of the calixarene sodium complex for inclusion of the solvent molecule in the calixarene hydrophobic cavity, with the exception of acetonitrile. Differences in complex stabilities in the explored solvents, apart from N,N-dimethylformamide and acetonitrile, could be mostly explained by taking into account solely the cation and complex solvation. A considerable solvent effect on the complexation equilibria was proven to be due to an interesting interplay between the transfer enthalpies and entropies of the reactants and the complexes formed.