Changes in Protonation Sites of 3-Styryl Derivatives of 7-(dialkylamino)-aza-coumarin Dyes Induced by Cucurbit[7]uril.

The incorporation of a guest, with different basic sites, into an organized system (host), such as macrocycles, could stabilize, detect, or promote the formation of a certain protomer. In this context, this work aimed to study the influence of cucurbit[7]uril (CB7) on dyes such as 7-(dimethylamino)-aza-coumarins, which have more than one basic site along their molecular structure. For this, three 3-styryl derivatives of 7-(dialkylamino)-aza-coumarin dyes (SAC1-3) were synthesized and characterized by NMR, ESI-HRMS and IR. The spectral behaviour of the SACs in the absence and presence of CB7 was studied. The results showed large shifts in the UV-vis spectrum in acid medium: a hypsochromic shift of ≈5400 cm-1 (SAC1-2) and ≈3500 cm-1 (SAC3) in the absence of CB7 and a bathochromic shift of ≈4500 cm-1 (SAC1-3) in the presence of CB7. The new absorptions at long and short wavelengths were assigned to the corresponding protomers by computational calculations at the density functional theory (DFT) level. Additionally, the binding mode was corroborated by molecular dynamics simulations. Findings revealed that in the presence of CB7 the heterocyclic nitrogen was preferably protonated instead of the dialkylamino group. Namely, CB7 induces a change in the protonation preference at the basic sites of the SACs, as consequence of the molecular recognition by the macrocycle.

Pseudorotaxane formation affected by stereo-electronic effects. A theoretical and experimental study.

We report a theoretical and experimental study on different complexes of pseudorotaxanes possessing pyridine axles. In order to evaluate the stereo-electronic effects of the methyl substituents in the pyridine ring, complexes with different substitution patterns were synthesized. In this way, it was possible to analyze the different behaviors of these complexes according to the positions of their methyl substituents. Combined techniques of molecular dynamics and quantum mechanical calculations with the help of molecular electrostatic potentials for a simpler visualization of the electronic effects were employed. We have sought experimental support of NMR spectroscopy analysis to corroborate the conclusions obtained from the molecular simulations. Our results not only clearly demonstrate that both electronic and steric effects play key roles in the feasibility of the formation of such complexes, but also the simulations reported here might predict the degree of difficulty of their formation. The combination of computational techniques employed here seems to be an excellent approach to be able to predict whether or not a complex can be formed and with what degree of difficulty. In addition, our experimental and theoretical results have allowed us to visualize the formation of external complexes in the rotaxanes reported here. In this case, the use of bolaforms with trimethylammonium groups at both ends was very useful to evaluate in detail the formation of the so-called external complexes in these systems.

Supramolecular Control of Reactivity toward Hydrolysis of 7-Diethylaminocoumarin Schiff Bases by Cucurbit[7]uril Encapsulation.

A series of aromatic Schiff bases, featuring 7-diethylamino-coumarin and with five different substituents at an adjacent phenyl ring, were synthesized and characterized. With the aim of assessing the stability of these dyes in acidic medium, their hydrolysis reactions were kinetically studied in the absence and presence of the macrocycle cucurbit[7]uril (CB[7]). Our results are consistent with a model containing three different forms of substrates (un-, mono-, and diprotonated) and three parallel reaction pathways. The pK a values and the rate constants were estimated and discussed in terms of the presence of a hydroxyl group at the ortho position and electron-releasing groups on the phenyl ring of the dyes. The kinetic study in the presence of CB[7] led to two different behaviors. Promotion of the reaction by CB[7] was observed for the hydrolysis of the Schiff bases containing only one coordination site toward the macrocycle. Conversely, an inhibitor effect was observed for the hydrolysis of a Schiff base with two coordination sites toward CB[7]. The latter effect could be explained with a model as a function of a prototropic tautomeric equilibrium and the formation of a 2:1 host/guest complex, which prevents the attack of water. Therefore, the kinetic results demonstrated a supramolecular control of the macrocycle toward the reactivity and stability of 7-diethylaminocoumarin Schiff bases in acidic medium.

Biocompatible Solvents and Ionic Liquid-Based Surfactants as Sustainable Components to Formulate Environmentally Friendly Organized Systems.

In this review, we deal with the formation and application of biocompatible water-in-oil microemulsions commonly known as reverse micelles (RMs). These RMs are extremely important to facilitate the dissolution of hydrophilic and hydrophobic compounds for biocompatibility in applications in drug delivery, food science, and nanomedicine. The combination of two wisely chosen types of compounds such as biocompatible non-polar solvents and ionic liquids (ILs) with amphiphilic character (surface-active ionic liquids, SAILs) can be used to generate organized systems that perfectly align with the Green Chemistry concepts. Thus, we describe the current state of SAILs (protic and aprotic) to prepare RMs using non-polar but safe solvents such as esters derived from fatty acids, among others. Moreover, the use of the biocompatible solvents as the external phase in RMs and microemulsions/nanoemulsions with the other commonly used biocompatible surfactants is detailed showing the diversity of preparations and important applications. As shown by multiple examples, the properties of the RMs can be modified by changes in the type of surfactant and/or external solvents but a key fact to note is that all these modifications generate novel systems with dissimilar properties. These interesting properties cannot be anticipated or extrapolated, and deep analysis is always required. Finally, the works presented provide valuable information about the use of biocompatible RMs, making them a green and promising alternative toward efficient and sustainable chemistry.

Cucurbit[7]uril as a Supramolecular Catalyst in Base-Catalyzed Reactions. Experimental and Theoretical Studies on Carbonate and Thiocarbonate Hydrolysis Reactions.

Cucurbit[7]uril (CB7) catalyzes the hydrolysis reaction of bis(4-nitrophenyl)carbonate (1) but inhibits that of bis(4-nitrophenyl)thiocarbonate (2). Two relevant CB7 effects are proposed, a base-catalyst mediated by the CB7 portal and an inhibitory role attributed to the lower interaction of the thiocarbonyl group with the solvent in the host cavity, respectively.

Hydrolysis Reactions of Two Benzoyl Chlorides as a Probe to Investigate Reverse Micelles Formed by the Ionic Liquid-Surfactant bmim-AOT.

In this work, two hydrolysis reactions were used as a probe to investigate the properties of reverse micelles (RMs) formed by the ionic liquid-surfactant 1-butyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate (bmim-AOT). The results were compared with those found for RMs generated with sodium 1,4-bis-2-ethylhexylsulfosuccinate (Na-AOT). As external nonpolar solvents, n-heptane (n-Hp), isopropyl myristate (IPM), and methyl laurate (ML) were used. Thus, the effect of changing the Na+ cation by bmim+ was analyzed, as well as the impact of the replacement of a conventional external nonpolar solvent by biocompatible solvents. The kinetics of the hydrolysis reactions of 4-methoxybenzoyl chloride (OMe) and 4-(trifluoromethyl)benzoyl chloride (CF3) were studied. The results indicate that the replacement of the Na+ counterion by bmim+ in AOT RMs alters the rates of reactions carried out in them and produces changes in the reaction mechanism. In bmim-AOT RMs, the bmim+ cation is located between the surfactant molecules; this has an important influence on the reaction intermediates' stability and, therefore, in the reaction rates and mechanisms. Also, the results indicate that when IPM is used as an external solvent instead of ML or n-Hp, interfacial water molecules have larger nucleophilicity due to the higher interface penetration of IPM.

Characterization of Reverse Micelles Formulated with the Ionic-Liquid-like Surfactant Bmim-AOT and Comparison with the Traditional Na-AOT: Dynamic Light Scattering, 1H NMR Spectroscopy, and Hydrolysis Reaction of Carbonate as a Probe.

The present study investigated how the presence of butylmethylimidazolium cation (bmim+) alters the interfacial properties of reverse micelles (RMs) created with the ionic liquid-like surfactant 1-butyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate (bmim-AOT), in comparison to sodium 1,4-bis-2-ethylhexylsulfosuccinate (Na-AOT) RMs, employing dynamic light scattering (DLS) and 1H NMR techniques. Moreover, through the hydrolysis reaction of bis(4-nitrophenyl)carbonate inside both RMs as reaction probe, interfacial properties changes were explored in more detail. The kinetic solvent isotope effect was also analyzed. Micellar systems were formed using n-heptane as external nonpolar solvent and water as the polar component. According to the DLS studies, water is encapsulated inside the organized media; however, a different tendency is observed depending on the cationic component of the surfactant. For Na-AOT system, the results suggest that the micellar shapes are probably spherical, while in the case of bmim-AOT, a transition from ellipsoidal to spherical micelles could be occurring when water is added. 1H NMR data show that water is structured differently when Na+ cation is replaced by bmim+; in bmim-AOT RMs, the interaction of water with the surfactant is weaker and the water hydrogen-bonding network is less disturbed than in Na-AOT RMs. Kinetic studies reveal that the hydrolysis reaction in bmim-AOT RMs was much more favorable in comparison to Na-AOT RMs. In addition, when water content decreases in bmim-AOT RMs, the hydrolysis reaction rate increases and the solvent isotope effect remains constant, while for Na-AOT solutions, both the reaction rate and the solvent isotope effect decrease. Our results indicate that bmim+ cation would be located in the surfactant layer in such a way the negative charge density in the interface is less than that in Na-AOT RMs, and the reaction is more favorable. Additionally, as 1H NMR studies reveal, the interfacial water molecules would be more available in bmim-AOT RMs to participate in the nucleophilic attack. Therefore, the present study evidences how the replacement of Na+ counterion by bmim+ alters the composition of the interface of AOT RMs.

Inhibitory and Cooperative Effects Regulated by pH in Host-Guest Complexation between Cationic Pillar[5]arene and Reactive 2-Carboxyphthalanilic Acid.

The study of host-guest complexation between reactive 2-carboxyphthalanilic acid (CPA) and two cationic pillararenes has been carried out. Host-guest complexation with significant kinetic effects was observed only with the smaller cavity size pillararene (P5A). Kinetics in the pH range 1.50-6.40, ESI-MS, 1H NMR titration, and ROESY experiments were performed to characterize the complexes. High binding stoichiometry (H:G2) was observed for all CPA protonation states. The system is pH-dependent, and inversion of cooperativity (negative to positive) occurs by increasing the dianionic CPA2- concentration (allosteric behavior). Toward physiological pH, association constant K1:1 does not change (104 M-1), and K1:2 increased from 102 to 104 M-1, as well as the inhibitory effect increased up to 222-fold. NMR results elucidated the structure of the complex and allowed us to create a map of H-H interactions that describes well the diversity and number of interactions in the complex.

Inclusion of Ethyl Acetoacetate Bearing 7-Hydroxycoumarin Dye by ß-Cyclodextrin and its Cooperative Assembly with Mercury(II) Ions: Spectroscopic and Molecular Modeling Studies.

The inclusion of the fluorescent organic dye, ethyl 3-(7-hydroxy-2-oxo-2H-chromen-3-yl)-3-oxopropanoate (1) by the host ß-cyclodextrin (ß-CD), and its response toward mercuric ions (Hg2+ ), was studied by UV/Vis, fluorescence, and 1 H NMR spectroscopic analyses, mass spectrometry and molecular modeling studies. 1 H NMR measurements together with molecular modeling studies for dye 1 demonstrate that it exhibits two tautomeric forms (keto and enol); however, when the dye is included into the ß-CD cavity, the enol form predominates. Moreover, by using spectroscopic and spectrometry techniques, a 1:1 stoichiometry was determined for the complexes formed between dye 1 (enol form) and ß-CD, with a binding constant (Kb1 =1.8×104 m-1 ) and for the dye 1 (keto form)-Hg2+ (Kb2 =2.3×103 m-1 ). Interestingly, in the presence of 1-ß-CD complex and mercuric ions, a ternary supramolecular system (Hg-1-ß-CD complex) was established, with a 1:1:1 stoichiometry and a Kb3 value of 4.3×103 m-1 , with the keto form of the dye being the only one present in this assembly. The three-component system provides a starting point for the development of novel and directed supramolecular assemblies.

Supramolecular phosphate transfer catalysis by pillar[5]arene.

A kinetic study on dinitrophenylphosphate monoester hydrolysis in the presence of a cationic pillararene, P5A, has been carried out. Formation of the supramolecular complex between phosphate ester and P5A has been studied by NMR showing complexation-induced upfield proton shifts indicative of aromatic ring inclusion in the pillararene cavity. Molecular dynamic calculations allow structure characterization for the 1 : 1 and 1 : 2 complexes. As a result of the supramolecular interaction both the acidity of DNPP and its hydrolysis rate constants are increased. Catalysis results from combination of both electrostatic stabilization reducing the negative electron density on the PO3(=) oxygens and monoester dianion destabilization by the steric effects of close NMe3(+) groups hindering the hydrogen-bonding with water and destabilising the monoester dianion.

Ionic liquids entrapped in reverse micelles as nanoreactors for bimolecular nucleophilic substitution reaction. Effect of the confinement on the chloride ion availability.

In this work was explored how the confinement of two ionic liquids (ILs), 1-butyl-3-methylimidazolium chloride (bmimCl) and 1-butyl-3-methylimidazolium tetrafluoroborate (bmimBF4), inside toluene/benzyl-n-hexadecyldimethylammonium chloride (BHDC) reverse micelles (RMs) affects the Cl(-) nucleophilicity on the bimolecular nucleophilic substitution (SN2) reaction between this anion and dimethyl-4-nitrophenylsulfonium trifluoromethanesulfonate. The results obtained show that, upon confinement, the ionic interactions between the ILs with the cationic surfactant polar head group and the surfactant counterion modify substantially the performance of both ILs as solvents. In toluene/BHDC/bmimCl RMs, the Cl(-) interacts strongly with bmim(+) (and/or BHD(+)) in such a way that its nucleophilicity is reduced in comparison with neat IL. In toluene/BHDC/bmimBF4 RMs, an ionic exchange equilibrium produces segregation of bmim(+) and BF4(-) ions, changing the composition of the RMs interface and affecting dramatically the Cl(-) availability. These results show the versatility of this kind of organized system to alter the ionic organization and influence on reaction rate when used as nanoreactors.

Redox-changes associated with the glutathione-dependent ability of the Cu(II)-GSSG complex to generate superoxide.

The intracellularly-occurring Cu(I)-glutathione complex (Cu(I)-[GSH](2)) has the ability to reduce molecular oxygen into superoxide. Removal of such radicals leads to the irreversible conversion of Cu(I)-[GSH](2) into the redox-inactive Cu(II)-GSSG complex. The present study addressed the potential of reduced glutathione, ascorbate and superoxide to reductively regenerate Cu(I)-[GSH](2) from Cu(II)-GSSG, and investigated the redox changes involved in such process. Results show that: (i) among the three tested reductants, only GSH is able to reduce the Cu(II) bound to GSSG; (ii) during the reduction of Cu(II)-GSSG, a Cu(I)-GSSG intermediate would be formed (supported here by Cu(I) and GSSG recovery data and by NMR studies); (iii) when GSH is present in a molar excess equal or greater than 1:3, the reduction of Cu(II)-GSSG into Cu(I)-[GSH](2) is quantitative and complete. Under such conditions, the Cu(II)-GSSG complex acquires a superoxide-generating capacity which is identical to that seen with the Cu(I)-[GSH](2) complex. Within cells, the concentrations of GSH are at least 2- to 3-fold order of magnitude higher than those expected for the Cu(II)-GSSG complex. Thus, we postulate that the interaction between GSH and Cu(II)-GSSG could be seen as a potential mechanism to regenerate continuously the Cu(I)-[GSH](2) complex and thereby affect the ability of the latter to generate superoxide.