Search Results (21)

In the quest of the pivotal origin of the very strong gas-phase proton basicity for some iminopyrrole derivatives, proposed in the literature on the basis of quantum chemical calculations, the full tautomeric and acid/base equilibria were investigated in vacuo for 2-aminopyrrole exhibiting enamino–imino tautomerism. Thermochemistry of these processes investigated at the Density Functional Theory (DFT) level indicates a lower stability for the imino than for the enamino tautomers. However, the imino N atom in the imino forms displays an exceptionally high basicity, particularly in the minor and rare tautomers containing at least one tautomeric proton at the pyrrole C atom. This explains why derivatives of CH tautomers (being free of prototropy) display exceptionally high gas-phase proton basicity. As predicted by the Maksić group using quantum chemical methods, these derivatives can be considered as good organic imino N-superbase candidates. Unfortunately, some other structures of iminopyrrole derivatives (proposed by the same group) possess labile protons, and, thus, exhibit prototropy, resulting in the transformation into the more stable but less basic aminopyrrole derivatives under synthesis conditions or acid/base equilibria measurements. Full article

Prototropic conversion (prototropy) for heterocyclic nucleobases was already signaled by Watson and Crick about seventy years ago as one of the reasons for nucleic acids mutations. This isomeric phenomenon has been investigated for neutral derivatives by means of both experimental and theoretical procedures, and their favored tautomers discussed in numerous articles published in the last fifty years. Protonation/deprotonation reactions in the gas phase have also been studied using both quantum-chemical calculations and experimental techniques. Some thermochemical parameters of these processes have been documented. However, prototropy has not always been taken into account in protonation/deprotonation reactions. Most frequently, tautomeric heterocycles have been treated as simple polyfunctional compounds without possible intramolecular protontransfers. Taking into account the lack of data for the complete tautomeric mixtures, quantum-chemical investigations have been undertaken by us about twenty-five years ago for prototropic heterosystems. In this work, the pyrimidine base uracil (U) was chosen. It possesses two identical exo groups (=O/OH) at the 2- and 4-positions, two labile (tautomeric) protons, and five conjugated sites (N1, N3, C5, O7, and O8). Different types of isomerism, prototropy and OH-rotation, were considered for the neutral, protonated, and deprotonated forms. Using quantum-chemical methods, thermochemical stabilities of all possible tautomers-rotamers were examined in vacuo and the potential isomers selected. The selected isomeric mixtures for the neutral and ionic forms were applied for the determination of the thermochemical parameters in the four-step acid/base equilibria: B²⁻ BH⁻ BH₂ BH₃⁺ BH₄²⁺, where BH₂ indicates U. For each step, the microscopic (kinetic) and macroscopic (thermodynamic) acid/base parameters were estimated, and sites of the proton gain and proton loss examined. The similarities and differences between the acid/base equilibria for uracil and other pyrimidine nucleobases were discussed. Full article

Push-pull imines with strong electron donor group(s) display exceptional basicity in the gas phase. Most of them do not exhibit prototropic tautomerism, and gas-phase acid-base equilibria have been already well described and reviewed. Some questions remain for tautomeric systems, particularly for their uncommon forms. As shown by quantum-chemical calculations, some often-neglected tautomers display higher basicity than the thermodynamically favored forms. However, their participation in tautomeric mixtures being in equilibrium is negligible, and their basicity can be impossible to measure in the gas phase by the equilibrium method. During this work, we examined the gas-phase proton basicity for some acyclic and cyclic push-pull organic bases containing the tautomeric amidine or guanidine group. By quantum-chemical calculations, we confirmed the existence of very low amounts of rare tautomeric forms, in particular, those bearing a methylidene (=CH₂) group. We also demonstrated that the alkyl derivatives of rare tautomers, being free of prototropy, can be good candidates as very strong push-pull C bases, i.e., bases protonated on the =CH₂ group. Full article

In this review, the complete tautomeric equilibria are derived for disubstituted pyrimidine nucleic acid bases starting from phenol, aniline, and their model compounds—monosubstituted aromatic azines. The differences in tautomeric preferences for isolated (gaseous) neutral pyrimidine bases and their model compounds are discussed in light of different functional groups, their positions within the six-membered ring, electronic effects, and intramolecular interactions. For the discussion of tautomeric preferences and for the analysis of internal effects, recent quantum-chemical results are taken into account and compared to some experimental ones. For each possible tautomer-rotamer of the title compounds, the bond length alternation, measured by means of the harmonic oscillator model of electron delocalization (HOMED) index, is examined. Significant HOMED similarities exist for mono- and disubstituted derivatives. The lack of parallelism between the geometric (HOMED) and energetic (ΔG) parameters for all possible isomers clearly shows that aromaticity is not the main factor that dictates tautomeric preferences for pyrimidine bases, particularly for uracil and thymine. The effects of one-electron loss (positive ionization) and one-electron gain (negative ionization) on prototropy and bond length alternation are also reviewed for pyrimidine bases and their models. Full article

This paper thoroughly explores the formation of Schiff bases derived from salicylaldehydes and a conformationally restricted amino alcohol (1-amino-2-indanol), as well as the generation of 1,3-oxazolidines, a key heterocyclic core present in numerous bioactive compounds. We provide enough evidences, both experimental-including crystallographic analyses and DFT-based calculations on imine/enamine tautomerism in the solid state and solution. In the course of imine formation, a pentacyclic oxazolidine–oxazine structure could be isolated with complete stereocontrol, whose configuration has been determined by merging theory and experiment. Mechanistic studies reveal that, although oxazolidines can be obtained under kinetic conditions, the prevalence of imines obeys to thermodynamic control as they are the most stable structures. The stereochemical outcome of imine cyclization under acylating conditions leads to formation of 2,4-trans-oxazolidines. Full article

Inter- and intra-molecular proton-transfers between functional groups in nucleobases play a principal role in their interactions (pairing) in nucleic acids. Although prototropic rearrangements (intramolecular proton-transfers) for neutral pyrimidine bases are well documented, they have not always been considered for their protonated and deprotonated forms. The complete isomeric mixtures in acid-base equilibria and in acidity–basicity parameters have not yet been examined. Taking into account the lack of literature and data, research into the question of prototropy for the ionic (protonated and deprotonated) forms has been undertaken in this work. For the purposes of this investigation, two isomeric pyrimidine bases (C—cytosine and iC—isocytosine) were chosen. They exhibit analogous (symmetrical) general acid-base equilibria (intermolecular proton-transfers). Being similar polyfunctional tautomeric systems, C and iC possess two labile protons and five conjugated tautomeric sites. However, positions of exo groups are different. Consequently, structural conversions such as prototropy, rotational, and geometrical isomerism of exo groups (=O/−OH and =NH/−NH₂) and their intramolecular interactions with endo groups (=N−/>NH) possible in neutral C and iC and in their ionic forms lead to some differences in compositions of isomeric mixtures. By application of quantum–chemical methods to the isolated (in vacuo) species, stability of all possible neutral and ionic isomers has been examined and the candidate isomers selected. The complete isomeric mixtures have been considered for the first time for di-deprotonated, mono-deprotonated, mono-protonated, and di-protonated forms. Protonation–deprotonation reactions have been analyzed in the gas phase that models non-polar environment. The gas-phase microscopic (kinetic) and macroscopic (thermodynamic) acidity–basicity parameters have been estimated for each step of acid-base equilibria. When proceeding from di-anion to di-cation in four steps of protonation–deprotonation reaction, the macroscopic proton affinities for C and iC differ by less than 10 kcal mol⁻¹. Their DFT-calculated values are as follows: 451 and 457, 340 and 339, 228 and 224, and 100 and 104 kcal mol⁻¹, respectively. Differences between the microscopic proton affinities for analogous isomers of C and iC seem to be larger for the exo than endo groups. Owing to variations of relative stabilities for neutral and ionic isomers, in some cases they are even larger than 10 kcal mol⁻¹. Full article

Edaravone, acting as a cerebral protective agent, is administered to treat acute brain infarction. Its poor solubility is addressed here by means of optimizing the composition of the aqueous choline chloride (ChCl)-based eutectic solvents prepared with ethylene glycol (EG) or glycerol (GL) in the three different designed solvents compositions. The slurry method was used for spectroscopic solubility determination in temperatures between 298.15 K and 313.15 K. Measurements confirmed that ethaline (ETA = ChCl:EG = 1:2) and glyceline (GLE = ChCl:GL = 1:2) are very effective solvents for edaravone. The solubility at 298.15 K in the optimal compositions was found to be equal x_E = 0.158 (c_E = 302.96 mg/mL) and x_E = 0.105 (c_E = 191.06 mg/mL) for glyceline and ethaline, respectively. In addition, it was documented that wetting of neat eutectic mixtures increases edaravone solubility which is a fortunate circumstance not only from the perspective of a solubility advantage but also addresses high hygroscopicity of eutectic mixtures. The aqueous mixture with 0.6 mole fraction of the optimal composition yielded solubility values at 298.15 K equal to x_E = 0.193 (c_E = 459.69 mg/mL) and x_E = 0.145 (c_E = 344.22 mg/mL) for glyceline and ethaline, respectively. Since GLE is a pharmaceutically acceptable solvent, it is possible to consider this as a potential new liquid form of this drug with a tunable dosage. In fact, the recommended amount of edaravone administered to patients can be easily achieved using the studied systems. The observed high solubility is interpreted in terms of intermolecular interactions computed using the Conductor-like Screening Model for Real Solvents (COSMO-RS) approach and corrected for accounting of electron correlation, zero-point vibrational energy and basis set superposition errors. Extensive conformational search allowed for identifying the most probable contacts, the thermodynamic and geometric features of which were collected and discussed. It was documented that edaravone can form stable dimers stabilized via stacking interactions between five-membered heterocyclic rings. In addition, edaravone can act as a hydrogen bond acceptor with all components of the studied systems with the highest affinities to ion pairs of ETA and GLE. Finally, the linear regression model was formulated, which can accurately estimate edaravone solubility utilizing molecular descriptors obtained from COSMO-RS computations. This enables the screening of new eutectic solvents for finding greener replacers of designed solvents. The theoretical analysis of tautomeric equilibria confirmed that keto-isomer edaravone is predominant in the bulk liquid phase of all considered deep eutectic solvents (DES). Full article

The equilibrium between different tautomers that can be colored or colorless is an important feature for rhodamine dyes. Presently, this phenomenon is mostly discussed for rhodamine B. Herein, we studied the tautomerism and acid–base dissociation (HR⁺ ⇄ R + H⁺) of a set of rhodamines in organic media. Form R is an equilibrium mixture of the colored zwitterion R^± and colorless lactone R⁰. Absorption spectra in 90 mass% aqueous acetone reflects the correlation between the dyes structure and the equilibrium constant, K_T = [R⁰]/[R^±]. Increase in the pK_a value on transferring from water to organic solvents confirms the highly polar character of the R^± tautomer. To reveal the role of the solvent nature, the tautomerism of an asymmetrical rhodamine, 2-(12-(diethyliminio)-2,3,5,6,7,12-hexahydro-1H-chromeno[2,3-f]pyrido[3,2,1-ij]quinolin-9-yl)benzoate, was examined in 14 media. This chain–ring tautomerism is an intramolecular acid–base reaction; the central carbon atom acts as a Lewis acid. The interaction with other Lewis acids, Li⁺, Ca²⁺, Mg²⁺, and La³⁺, results in rupture of lactone cycle. In polar solvents, lactones undergo photocleavage resulting in formation of highly fluorescent R^±, whereas the blue fluorescence and abnormally high Stokes shift in low-polar media may be explained either by another photoreaction or by spiroconjugation and charge transfer in the exited state. Full article

The paper briefly summarizes methods to determine the structure of β-diketones with emphasis on NMR methods. Density functional calculations are also briefly treated. Emphasis is on the tautomeric equilibria of β-diketones in relation to biological effects. Relevant physical parameters such as acidity and solubility are treated. A series of biologically active molecules are treated with respect to structure (tautomerism). Characteristic molecules or groups of molecules are usnic acids, tetramic and tetronic acids, o-hydroxydibenzoylmethanes, curcumines, lupulones, and hyperforines. Full article

This review outlines methods to investigate the structure of natural products with emphasis on intramolecular hydrogen bonding, tautomerism and ionic structures using NMR techniques. The focus is on 1H chemical shifts, isotope effects on chemical shifts and diffusion ordered spectroscopy. In addition, density functional theory calculations are performed to support NMR results. The review demonstrates how hydrogen bonding may lead to specific structures and how chemical equilibria, as well as tautomeric equilibria and ionic structures, can be detected. All these features are important for biological activity and a prerequisite for correct docking experiments and future use as drugs. Full article

An implicit account of the solvent effect can be carried out using traditional static quantum chemistry calculations by applying an external electric field to the studied molecular system. This approach allows one to distinguish between the effects of the macroscopic reaction field of the solvent and specific solute–solvent interactions. In this study, we report on the dependence of the simulation results on the use of the polarizable continuum approximation and on the importance of the solvent effect in nonpolar solvents. The latter was demonstrated using experimental data on tautomeric equilibria between the pyridone and hydroxypyridine forms of 2,6-di-tert-butyl-4-hydroxy-pyridine in cyclohexane and chloroform. Full article

Ionic equilibrium of 22 hydroxyxanthenes, including halogen and nitro derivatives of fluorescein, and their thio- and aza analogues, were studied spectrophotometrically in micellar solutions of cetyltrimethylammonium chloride at ionic strength of the bulk phase 4.0 M KCl. This micellar pseudophase is characterized by the electrostatic surface potential of +(15–16) mV and the $E_{\mathrm{T}}^{\mathrm{N}}$ value of 0.623. In the case of dyes bearing the COOH group, colorless lactone is the predominant tautomer of the molecular form H₂R. A new classification of fluoresceins is developed. The dyes were divided into four groups based on the nature of tautomerism of the anions. In the case of the fluorescein type, the monoanions HR⁻ exist predominantly as “carboxylate” tautomers, with ionized carboxylic and non–ionized hydroxylic group. For the dyes of the eosin type, the situation is opposite, while for the intervening type of compounds, the concentrations of the two tautomers are comparable. Dyes capable of forming lactone anions HR⁻ were classified as the fourth type. For some of them, even the dianion R²⁻ exists as a lactone. The relationship between the stepwise ionization constants, $K_{\mathrm{a}1}/K_{\mathrm{a}2}$, varies from 1.3 to 1.07 × 10⁵ and is determined by the state of tautomeric equilibrium of molecules and ions. Full article

The energy involved in the structural switching of acyl and hydroxyl substituents in the title compounds was evaluated combining experimental and computational studies. Combustion calorimetry and Knudsen effusion techniques were used to determine the enthalpies of formation, in the crystalline state, and of sublimation, respectively. The gas-phase enthalpy of formation of both isomers was derived combining these two experimental data. Concerning the computational study, the G3(MP2)//B3LYP composite method was used to optimize and determine the energy of the isomers in the gaseous state. From a set of hypothetical reactions it has been possible to estimate the gas-phase enthalpy of formation of the title compounds. The good agreement between the experimental and computational gas-phase enthalpies of formation of the 1-acetyl-2-naphthol and 2-acetyl-1-naphthol isomers, provided the confidence for extending the computational study to the 2-acetyl-3-naphthol isomer. The structural rearrangement of the substituents in position 1 and 2 in the naphthalene ring and the energy of the intramolecular hydrogen bond are the factors responsible for the energetic differences exhibited by the isomers. The gas phase tautomeric keto ↔ enol equilibria of the o-acetylnaphthol isomers were analyzed using the Boltzmann’s distribution. Full article

A series of disubstituted 1H-pyrazoles with methyl (1), amino (2), and nitro (3) groups, as well as ester (a) or amide (b) groups in positions 3 and 5 was synthesized, and annular tautomerism was investigated using X-ray, theoretical calculations, NMR, and FT-IR methods. The X-ray experiment in the crystal state showed for the compounds with methyl (1a, 1b) and amino (2b) groups the tautomer with ester or amide groups at position 3 (tautomer 3), but for those with a nitro group (3b, 4), tautomer 5. Similar results were obtained in solution by NMR NOE experiments in CDCl₃, DMSO-d₆, and CD₃OD solvents. However, tautomer equilibrium was observed for 2b in DMSO. The FT-IR spectra in chloroform and acetonitrile showed equilibria, which can be ascribed to conformational changes of the cis/trans arrangement of the ester/amide group and pyrazole ring. Theoretical analysis using the M06-2X/6-311++G(d,p) method (in vacuo, chloroform, acetonitrile, and water) and measurement of aromaticity (NICS) showed dependence on internal hydrogen bonds, the influence of the environment, and the effect of the substituent. These factors, pyrazole aromaticity and intra- and inter-molecular interactions, seem to have a considerable influence on the choice of tautomer. Full article

This follow-up paper completes the author’s investigations to explore the in-solution structural preferences and relative free energies of all OH-substituted oxazole, thiazole, isoxazole, and isothiazole systems. The polarizable continuum dielectric solvent method calculations in the integral-equation formalism (IEF-PCM) were performed at the DFT/B97D/aug-cc-pv(q+(d))z level for the stable neutral tautomers with geometries optimized in dichloromethane and aqueous solution. With the exception of the predictions for the predominant tautomers of the 3OH isoxazole and isothiazole, the results of the IEF-PCM calculations for identifying the most stable tautomer of the given species in the two selected solvents agreed with those from experimental investigations. The calculations predict that the hydroxy proton, with the exception for the 4OH isoxazole and 4OH isothiazole, moves preferentially to the ring nitrogen or to a ring carbon atom in parallel with the development of a C=O group. The remaining, low-fraction OH tautomers will not be observable in the equilibrium compositions. Relative solvation free energies obtained by the free energy perturbation method implemented in Monte Carlo simulations are in moderate accord with the IEF-PCM results, but consideration of the ΔG_solv/MC values in calculating ΔG^s_tot maintains the tautomeric preferences. It was revealed from the Monte Carlo solution structure analyses that the S atom is not a hydrogen-bond acceptor in any OH-substituted thiazole or isothiazole, and the OH-substituted isoxazole and oxazole ring oxygens may act as a weak hydrogen-bond acceptor at most. The molecules form 1.0−3.4 solute−water hydrogen bonds in generally unexplored numbers at some specific solute sites. Nonetheless, hydrogen-bond formation is favorable with the NH, C=O and OH groups. Full article