Reliable and accurate prediction of basic pK[Formula: see text] values in nitrogen compounds: the pK[Formula: see text] shift in supramolecular systems as a case study.

This article presents a quantitative structure-activity relationship (QSAR) approach for predicting the acid dissociation constant (pK[Formula: see text]) of nitrogenous compounds, including those within supramolecular complexes based on cucurbiturils. The model combines low-cost quantum mechanical calculations with QSAR methodology and linear regressions to achieve accurate predictions for a broad range of nitrogen-containing compounds. The model was developed using a diverse dataset of 130 nitrogenous compounds and exhibits excellent predictive performance, with a high coefficient of determination (R[Formula: see text]) of 0.9905, low standard error (s) of 0.3066, and high Fisher statistic (F) of 2142. The model outperforms existing methods, such as Chemaxon software and previous studies, in terms of accuracy and its ability to handle heterogeneous datasets. External validation on pharmaceutical ingredients, dyes, and supramolecular complexes based on cucurbiturils confirms the reliability of the model. To enhance usability, a script-like tool has been developed, providing a streamlined process for users to access the model. This study represents a significant advancement in pK[Formula: see text] prediction, offering valuable insights for drug design and supramolecular system optimization.

Influence of ß-Cyclodextrin Methylation on Host-Guest Complex Stability: A Theoretical Study of Intra- and Intermolecular Interactions as Well as Host Dimer Formation.

Understanding the non-covalent interactions in host-guest complexes is crucial to their stability, design and applications. Here, we use density functional theory to compare the ability of ß-cyclodextrin (ß-CD) and heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD) to encapsulate the model guest phenol. For both macrocycles, we quantify the intramolecular interactions before and after the formation of the complex, as well as the intermolecular host-guest and host-host dimer interactions. These are individually classified as van der Waals interactions or hydrogen bonds, respectively. The results show a stronger intramolecular binding energy of ß-CD, with the absolute difference being -5.53 kcal/mol relative to DM-ß-CD. Consequently, the intermolecular interactions of both cyclodextrins with phenol are affected, such that the free binding energy calculated for the DM-ß-CD/phenol complex (-5.23 kcal/mol) is ≈50% more negative than for the complex with ß-CD (-2.62 kcal/mol). The latter is in excellent agreement with the experimental data (-2.69 kcal/mol), which validates the level of theory (B97-3c) used. Taken together, the methylation of ß-CD increases the stability of the host-guest complex with the here studied guest phenol through stronger van der Waals interactions and hydrogen bonds. We attribute this to the disruption of the hydrogen bond network in the primary face of ß-CD upon methylation, which influences the flexibility of the host toward the guest as well as the strength of the intermolecular interactions. Our work provides fundamental insights into the impact of different non-covalent interactions on host-guest stability, and we suggest that this theoretical framework can be adapted to other host-guest complexes to evaluate and quantify their non-covalent interactions.

Exploring the behavior of Candida antarctica lipase B in aqueous mixtures of an imidazolium ionic liquid and its surfactant analogue.

The performance of Candida antarctica lipase B (CALB) has been evaluated in 1-butyl-3-methylimidazolium tetrafluoroborate (BMIMBF4)/water mixtures in a wide range of molar fractions (χBMIMBF4) with and without 1-dodecyl-3-methylimidazolium tetrafluoroborate (C12-MIMBF4), a surfactant derived from BMIMBF4. The main aim of this work is to evaluate the influence of χBMIMBF4 over micellar aggregates to assess the activity of enzymatic reactions. The investigated reaction corresponds to the hydrolysis of the substrate p-nitrophenyl laureate in each χBMIMBF4. The kinetic study for χBMIMBF4 at around 0.2 proved to be a border point in enzymatic activity. At χBMIMBF4 = 0.1, the lipase activity increases in the presence of C12-MIMBF4. However, at higher concentrations, BMIMBF4 has a negligible effect over the lipase activity. These results suggest specific interactions between water and BMIMBF4 molecules in relation to CALB. This research highlights the superactivity phenomenon driven by the reaction media and the micelle interface. In this interfacial interaction, BMIMBF4 acts directly on the changes induced on the enzyme upon its interaction with the micellar interface. This study opens a green perspective toward the biocatalysis field.

Kinetics and Reaction Mechanism of Biothiols Involved in SNAr Reactions: An Experimental Study.

Few kinetic parameters, or reaction rates, are known up to date in detail about 1-chloro and 1-fluoro-2,4-dinitrobenzene (ClDNB and FDNB, respectively) with a series of biothiols in aqueous media. These biological nucleophiles with thiol groups have been widely used as a reference in nucleophile reactivity assays due to their prevalence and cellular abundance. The main aim of this study was to elucidate the reaction mechanism based on Brönsted-type plots and reactivity patterns of the electrophile/nucleophile pairs. A complete kinetic study was performed in terms of the comparison of Brönsted-type slope parameters (ß nuc) for the reactions and was used for assigning the mechanism and the rate-determining step associated with the reaction route. A mass spectrometry analysis demonstrated that the nucleophilic center of the biothiols is the -SH group and there is only one kinetic product. The kinetic study suggests that the reaction mechanism might be the borderline between concerted and stepwise pathways. An amine-enol equilibrium for the most reactive nucleophiles appears to be the main determining factor controlling the nucleophilic attack in the nucleophilic aromatic substitution reactions investigated, highlighting the anionic form for these nucleophiles. This amine-enol equilibrium involves a hydrogen bond which stabilizes the intermediate species in the reaction pathway. Thus, intramolecular bonds are formed and enhance the nucleophilic strength through the contribution of the solvent surrounding the electrophile/nucleophile pairs. Finally, we highlight the importance of the formation of electrophile/nucleophile adducts that could modify structures and/or functions of biological systems with potential toxic effects. Therefore, it is essential to know all these kinetic and reactivity patterns and their incidence on other studies.

Gutmann's Donor and Acceptor Numbers for Ionic Liquids and Deep Eutectic Solvents.

An experimental and computational methodology for the analysis of the Lewis acid/base responses of ionic liquids (ILs) and deep eutectic solvents (DES) is proposed. It is based on the donor and acceptor of the electronic charge ability of Lewis acid and bases concepts (donicity and acceptor numbers, DN and AN, respectively) proposed by Viktor Gutmann. The binding enthalpy between the IL/DES with the probe antimony pentachloride (SbCl5) in dichloroethane displays good correlations with experimental data. This approach could serve as a first approximation to predict the responses to H-bonding abilities of new IL or DES. Although useful, the problems encountered to model the electron AN of these solvents limit the usefulness of the approach to completely describe their polarity properties. The experimental data were recorded using UV-Vis spectroscopy for a wide range of ILs and a couple of DES. Two reactions were used as benchmarks to test the reliability of the DN model to discuss the reactivity of real systems in these neoteric solvents.

How the Nature of an Alpha-Nucleophile Determines a Brønsted Type-Plot and Its Reaction Pathways. An Experimental Study.

The reactions between 2-chloro-5-nitro pyrimidine with a serie of α-nucleophile derivatives were kinetically evaluated. The kinetic study was carried out in aqueous media and the data shown an unusual split on the Brønsted type-plot, opening a controversial discussion based on reactivities and possible reaction pathways. These split Brønsted type-plots are discussed over the hypothetical transition state (TS) structures associated to concerted or stepwise mechanisms with emphasis on hydrogen bond interactions between electrophile/nucleophile pair able to determine the reactivities and the plausible reaction routes.

Experimental Analyses Emphasize the Stability of the Meisenheimer Complex in a SNAr Reaction Toward Trends in Reaction Pathways.

The mechanism of SNAr reactions between 2-chloro-5-nitropyrimidine with primary and secondary alicyclic amines, respectively, have been studied by kinetic measurements. The kinetic data obtained in aqueous media opens a controversial discussion based on Brönsted-type plots analysis. The first approach based on the kinetic data reveals a non-catalyzed pathway. Then, the subtlety of the mathematical treatment of the kinetic data is discussed over a concerted or stepwise mechanism, respectively.

Activation of Electrophile/Nucleophile Pair by a Nucleophilic and Electrophilic Solvation in a SNAr Reaction.

Nucleophilic aromatic substitution reactions of 4-chloroquinazoline toward aniline and hydrazine were used as a model system to experimentally show that a substrate bearing heteroatoms on the aromatic ring as substituent is able to establish intramolecular hydrogen bond which may be activated by the reaction media and/or the nature of the nucleophile.

Gutmann's Donor Numbers Correctly Assess the Effect of the Solvent on the Kinetics of SN Ar Reactions in Ionic Liquids.

We report an experimental study on the effect of solvents on the model SN Ar reaction between 1-chloro-2,4-dinitrobenzene and morpholine in a series of pure ionic liquids (IL). A significant catalytic effect is observed with reference to the same reaction run in water, acetonitrile, and other conventional solvents. The series of IL considered include the anions, NTf2 (-) , DCN(-) , SCN(-) , CF3 SO3 (-) , PF6 (-) , and FAP(-) with the series of cations 1-butyl-3-methyl-imidazolium ([BMIM](+) ), 1-ethyl-3-methyl-imidazolium ([EMIM](+) ), 1-butyl-2,3-dimethyl-imidazolium ([BM2 IM](+) ), and 1-butyl-1-methyl-pyrrolidinium ([BMPyr](+) ). The observed solvent effects can be attributed to an "anion effect". The anion effect appears related to the anion size (polarizability) and their hydrogen-bonding (HB) abilities to the substrate. These results have been confirmed by performing a comparison of the rate constants with Gutmann's donicity numbers (DNs). The good correlation between rate constants and DN emphasizes the major role of charge transfer from the anion to the substrate.

Hydrogen bond contribution to preferential solvation in S(N)Ar reactions.

Preferential solvation in aromatic nucleophilic substitution reactions is discussed using a kinetic study complemented with quantum chemical calculations. The model system is the reaction of a series of secondary alicyclic amines toward phenyl 2,4,6-trinitrophenyl ether in aqueous ethanol mixtures of different compositions. From solvent effect studies, it is found that only piperidine is sensitive to solvation effects, a result that may be traced to the polarity of the solvent composition in the ethanol/water mixture, which points to a specific electrophilic solvation in the aqueous phase.

Specific nucleophile-electrophile interactions in nucleophilic aromatic substitutions.

We herein report results obtained from an integrated experimental and theoretical study on aromatic nucleophilic substitution (S(N)Ar) reactions of a series of amines towards 1-fluoro-2,4-dinitrobenzene in water. Specific nucleophile-electrophile interactions in the title reactions have been kinetically evaluated. The whole series undergoes S(N)Ar reactions where the formation of the Meisenheimer complex is rate determining. Theoretical studies concerning specific interactions are discussed in detail. It is found that H-bonding effects along the intrinsic reaction coordinate profile promote the activation of both the electrophile and the nucleophile. Using these results, it is possible to establish a hierarchy of reactivity that is in agreement with the experimental data. Second order energy perturbation energy analysis highlights the strong interaction between the ortho-nitro group and the acidic hydrogen atom of the amine. The present study strongly suggests that any theoretical analysis must be performed at the activated transition state structure, because the static model developed around the reactant states hides most of the relevant specific interactions that characterize the aromatic substitution process.

Reactivity indices profile: a companion tool of the potential energy surface for the analysis of reaction mechanisms. Nucleophilic aromatic substitution reactions as test case.

We herein report on the usefulness of the reactivity indices profiles along a reaction coordinate. The model is tested to fully describe the reaction mechanism of the title reactions. Group nucleophilicity and electrophilicity profiles help describe the bond-breaking/bond-formation processes and the intramolecular electron density reorganization. The reactivity indices' profile analysis is consistently complemented with hydrogen bonding (HB) effects along the reaction coordinate: the final outcome of the reaction is determined by the stage at which the HB complex can be formed. Transition-state structures located for six reactions studied, including the charged nucleophile thiocyanate, show that the main stabilizing interaction is that formed between the hydrogen atom of the nucleophile and the o-NO(2) group. This result discards the role of HB interaction between the nucleophile and the leaving group previously proposed in the literature.

Are electrophilicity and electrofugality related concepts? A density functional theory study.

It is proposed that the electrofugality of a fragment within a molecule is determined by its group nucleophilicity. The variation of electrofugality should be tightly related to the electron releasing ability of the substituent attached to the electrofuge moiety. This contribution closes the set of relationships between philicity and fugality quantities: while nucleofugality appears related to the group electrophilicity of the leaving group, electrofugality is related to the group nucleophilicity of the permanent group.

Experimental and theoretical studies on the nucleofugality patterns in the aminolysis and phenolysis of S-aryl O-aryl thiocarbonates.

The reactions of S-phenyl, S-(4-chlorophenyl), and S-(2,3,4,5,6-pentafluorophenyl) 4-nitrophenyl thiocarbonates (9, 11, and 16, respectively) with a series of secondary alicyclic (SA) amines and those of S-(4-methylphenyl) 4-nitrophenyl thiocarbonate (8) and compounds 9 and 11 with a series of phenols are subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M. The reactions were followed spectrophotometrically. Under nucleophile excess, pseudo-first-order rate coefficients (k(obsd)) were found. For all these reactions, plots of k(obsd) vs. free amine or phenoxide anion concentration at constant pH are linear, the slope (k(N)) being independent of pH. The Brønsted-type plots (log k(N) vs. pK(a) of the conjugate acids of the nucleophiles) for the aminolysis of 9, 11, and 16 are linear with slopes beta = 0.85, 0.90, and 0.67, respectively. The two former slopes are consistent with a stepwise mechanism, through a zwitterionic tetrahedral intermediate, which breaking to products is rate determining. The latter beta value is consistent with a concerted mechanism. The Brønsted-type plots for the phenolysis of thiocarbonates 8, 9, and 11 are linear with slopes beta = 0.62, 0.70, and 0.69, respectively. These beta values and the absence of curvature at pK(a) = 7.5 confirm a concerted mechanism. In all these reactions, except those of 16, the main nucleofuge is 4-nitrophenoxide, being the thio benzenethiolate the minor nucleofuge. For the reactions of thiocarbonate 16 the main nucleofuge is pentafluorobenzenethiolate whereas little 4-nitrophenoxide was found. The reactions of two SA amines with S-(3-chlorophenyl) 4-nitrophenyl thiocarbonate (10) were subjected to product analysis, showing 60% 4-nitrophenoxide and 40% 3-chlorobenzenethiolate. The study is completed with a theoretical analysis based on the group electrophilicity index, a reactivity descriptor that may be taken as a measure of the ability of a group or fragment to depart from a molecule with the bonding electron pair. The theoretical analysis is in accordance with the experimental results obtained and predicts relative nucleofugalities of O-aryl vs. S-aryl groups in a series of diaryl thiocarbonates not experimentally evaluated to date.

Structure-reactivity relationships for electrophilic sugars in interaction with nucleophilic biological targets.

The global electrophilicity index that incorporates electrostatic and polarizability contributions shows a quantitative correlation with antiviral and cytotoxic activities of electrophilic sugars. The model is applied to a series of compounds that behave as Michael acceptors in interaction with biological nucleophilic targets.

Relationships between the electrophilicity index and experimental rate coefficients for the aminolysis of thiolcarbonates and dithiocarbonates.

Quantitative relationships are reported between the global electrophilicity index and the experimental rate coefficients for the reactions of thiolcarbonates and dithiocarbonates with piperidine. The validated scale of electrophilicity is then used to rationalize the reaction mechanisms of these systems. This scale also makes it possible to predict both rate coefficients and Hammett substituent constants for a series of systems that have not been experimentally evaluated to date.