Tautomeric Equilibrium Constants Research Articles

Structural characterization and keto-enol tautomerization of 4-substituted pyrazolone derivatives with DFT approach

The synthesis of two pyrazolone derivative compounds, PYR-I(4-Acetyl-1-(4-chlorophenyl)-3-isopropyl-1H-pyrazol-5(4H)-one) and PYR-II1-(4-Chlorophenyl))-3-isopropyl-5-oxo-4,5-5-dihydro-1H-pyrazole-4-carbaldehyde, their characterization by FT-IR, NMR, UV–Vis and GC-MS techniques, and the evaluation of the keto-enol tautomerization process of the structures along with the DFT approach and spectral data were reported in this paper. Spectral findings indicated that PYR-I was stable at the keto state. The IR spectrum recorded in solid form showed that the PYR-II structure was stable in the enol state, while the NMR spectrum in the solution medium showed that it was stable in the keto state. DFT-based analyses were realized with the B3LYP hybrid functional and the 6–311++G(d,p) basis set. The modelled keto, transition and enol state molecular geometries of structures were optimized in the gas phase and different solvent media and the total energy and dipole moment values were investigated at the specified theoretical level. The possible keto-enol tautomerism mechanism of the structures was evaluated through some thermodynamic parameters such as the difference in free Gibbs energy (ΔG), enthalpy (ΔH), entropy (ΔS), and predictive tautomeric equilibrium constants (Keq), acidity constants (pKa) and percentages of tautomers at 298.15 K and 1 atm pressure. The results of these analyses based on the DFT approach indicated that the keto-enol tautomer equilibrium heavily favours the keto form for PYR-I and the enol form for PYR-II in all cases. Moreover, natural bond orbital (NBO) analysis was performed for the tautomers, and the chemical reactivity profiles of the most stable tautomers were examined with the values of frontier molecular orbital energy and some reactivity descriptors.

How Hydrogen Bonding Amplifies Isomeric Differences in Pyridones toward Strong Changes in Acidity and Tautomerism.

Steric hindrance of hydration and hydrogen bond enhancement by localized charges have been identified as key factors for the massive chemical differences between the hydroxypyridine/pyridone isomers in aqueous solution. While all isomers occur mainly in the hydroxypyridine form in the gas phase, they differ by more than 3 orders of magnitude both in their acidity and tautomeric equilibrium constants upon hydration. By monitoring the electronic and solvation structures as a function of the protonation state and the O– substitution position on the pyridine ring, the amplification of the isomeric differences in aqueous solution has been investigated. Near-edge X-ray absorption fine structure (NEXAFS) measurements at the N K-edge served as the probe of the chemical state. The combination of molecular dynamics simulations, complete active space self-consistent field (CASSCF), and time-dependent density functional theory (TD-DFT) spectral calculations contributes to unraveling the principles of tautomerism and acidity in multiple biochemical systems based on tautomerism.

Crystal structure and vibrational spectra of salts of 1H-pyrazole-1-carboxamidine and its protonation route

Crystal structures of five salts of 1H-pyrazole-1-carboxamidine, PyCA, with various inorganic acids were determined, (HPyCA)Cl, (HPyCA)Cl·H2O, (HPyCA)Br, (HPyCA)2(I)I3, and (HPyCA)HSO4. Theoretical calculations of the protonation route of PyCA showed that the cationic form present in the studied crystals is energetically privileged. Tautomeric equilibrium constants indicated two isomers as the most stable neutral forms. Calculations for two other tautomers failed resulting in pyrazole and carbodiimid tautomer of cyanamide. Such decomposition is important in a view of guanylation reaction. Hydrogen bonding patterns were studied by means of the graph-set approach. Similarities of the patterns in different crystal structures were demonstrated by the algebraic relations between descriptors of the patterns. The strength of hydrogen bonding network in the crystals was assessed analyzing vibrational spectra. The bands were assigned on the basis of theoretical calculations for the complex [(HPyCA)2Cl4]2– ion and potential energy distribution analysis. The strength of hydrogen bonds was set in the following ascending series (HPyCA)2(I)I3 (4) < (HPyCA)Br (3) < (HPyCA)Cl (1) < (HPyCA)Cl·H2O (2) < (HPyCA)HSO4 (5).

Prediction of the tautomer stability and acidity of phenacylpyridines in aqueous solution

In this work, the aqueous acidity and tautomeric equilibrium constants are predicted in a systematic manner for the family of 2-, 3- and 4-phenacylpyridines which exhibit simultaneous keto–enol and imine–enamine tautomerism. The computational approach is based on electronic structure methods rooted in density functional theory, on an implicit SMD solvation model, and on thermodynamic cycles. In some instances, the high-quality hybrid CBS-QB3 method is used to obtain accurate gas-phase Gibbs free energies. The cationic, neutral, anionic and zwitterionic states of phenacylpyridines are considered, subject to a careful conformational analysis. Provided that a flexible enough basis set is used, estimated aqueous $${\text{p}}K_{{\mathrm{a}}}$$ and $${\text{p}}K_{{\mathrm{t}}}$$ values based on direct thermodynamic cycle correlate well with experimental data and show a reasonable quantitative agreement. On the other hand, it is found that the proton exchange scheme does not improve the accuracy of the predictions and different reference compounds are needed for each different type of the acidic site. Therefore, the errors herein are beyond systematic control. We use our results to present a brief discussion of the factors influencing the accuracy for the prediction of $${\text{p}}K_{{\mathrm{a}}}$$ and $${\text{p}}K_{{\mathrm{t}}}$$ for phenacylpyridines and presumably for other tautomeric compounds with multiple acidic centers.

Conjugated Quantitative Structure-Property Relationship Models: Application to Simultaneous Prediction of Tautomeric Equilibrium Constants and Acidity of Molecules.

Here, we describe a concept of conjugated models for several properties (activities) linked by a strict mathematical relationship. This relationship can be directly integrated analytically into the ridge regression (RR) algorithm or accounted for in a special case of "twin" neural networks (NN). Developed approaches were applied to the modeling of the logarithm of the prototropic tautomeric constant (logKT) which can be expressed as the difference between the acidity constants (pKa) of two related tautomers. Both conjugated and individual RR and NN models for logKT and pKa were developed. The modeling set included 639 tautomeric constants and 2371 acidity constants of organic molecules in various solvents. A descriptor vector for each reaction resulted from the concatenation of structural descriptors and some parameters for reaction conditions. For the former, atom-centered substructural fragments describing acid sites in tautomer molecules were used. The latter were automatically identified using the condensed graph of reaction approach. Conjugated models performed similarly to the best individual models for logKT and pKa. At the same time, the physically grounded relationship between logKT and pKa was respected only for conjugated but not individual models.

Halogenation and μH Tautomerism of 7-Benzyl-7,8-dicarba-nido-undecaborate(−1) Anion

Deboration of 1-PhCH2-1,2-C2B10H11 by heating in ethanolic potassium hydroxide afforded Me4N+ [7-PhCH2-7,8-C2B9H11]− which was treated with excess halosuccinimide (NCS, NBS) in acetonitrile or with elemental iodine or bromine in methanol to obtain Me4N+ [7-PhCH2-9,11-X2-7,8-C2B9H9]− (X = Cl, Br, I). The reaction of 1-PhCH2-1,2-C2B10H11 with an equimolar amount of iodine gave a mixture of Me4N+·[7-PhCH2-11-I-7,8-C2B9H10]- and Me4N+[7-C6H5CH2-9-I-7,8-C2B9H10]− at a ratio 1:1.8 due to steric effect of the benzyl substituent. The 11B chemical shifts of each μ-H tautomer of Me4N+ [7-PhCH2-9,11-X2-7,8-C2B9H9]− (X = H, F, Cl, Br, I) were calculated at the DFT level of theory, and their contributions to the average 11B NMR spectrum and the corresponding tautomeric equilibrium constants were determined.

Ring-Chain Tautomerism of the Condensation Products of 2-Mercaptobenzohydrazide with Aliphatic and Aromatic Aldehydes: Influence of Electronic and Steric Factors

It has been shown by 1H and 13C NMR spectroscopy that 2-mercaptobenzoyl-hydrazones of aliphatic and aromatic aldehydes exist in solution as tautomeric mixtures of linear and cyclic benzo-1,3,4-thiadiazepine forms. The linear hydrazone form is represented by (E,E')-and (E,Z')-conformational isomers, differing in the disposition relative to the amide C–N bond. Growing bulk of the alkyl substituent at the C=N bond of the aliphatic aldehydes derivatives decreases the fraction of the cyclic tautomer; therewith the logarithms of the constants of the chain-ring tautomeric equilibrium correlate with the ES steric constants of the alkyl substituents. In the series of the aromatic aldehydes 2-mercaptobenzoylhydrazones the linear tautomer prevails, and the logarithms of the tautomeric equilibrium constants KT correlate with the σ-constants of the substituents in the aromatic nucleus.

Electronic effects on keto–enol tautomerism of p-substituted aryl-1,3-diketone malonates

Electronic effects on keto–enol tautomerism of 1-(p-substituted aryl)-1,3-diketone malonates 1–10 were determined and established by NMR-Hammett linear free energy relationships. In addition, tautomeric equilibrium constants were determined for the title compounds by 1H NMR in DMSO-d6, showing an increasing to diketo tautomer with the increasing in the temperature. In this context, the enol form becomes less stable with increasing temperature suggesting that the intramolecular hydrogen bonding of the cis enol-keto form are increasingly broken at higher temperatures. In general, the enolic form (rather than the keto) is the most stable conformation due to its six member cyclic structure fulfilled by an internal O–H … O hydrogen bond.

Computational Study of the Stability of Tautomers and equilibrium constants of Cyanuric acid (CA) in Different solvents.

In the present investigation, the tautomeric and equilibrium of Cyanuric acid has been studied using Hartifock (HF) method in the gas phase and different solvents using the PCM model. The relative energies of these tautomers have been calculated at the HF level of theory using 6-311++ G (d,p) basis set. Energetics and relative stabilities of the tautomers were compared and analyzed in both the gaseous and different solvents. The results indicate that the keto tautomer (CA1) is the most stable form in the gas phase and other solvents. The order of stability of isomers was found to be CA1 &gt; CA3&gt; CA11&gt; CA2&gt; CA6&gt; CA10&gt; CA7&gt; CA4&gt; CA5&gt; CA9&gt;CA8. Having the largest dipole moment the CA8 tautomer is expected to have the strongest interaction with polar solvents. The HF method calculated tautomeric equilibrium constants with respect to the most stable tautomer CA1 of Cyanuric acid both in the gas and in different solvents. The of the equilibrium constants calculated starting from the general outline of interconversion.

Hartree–Fock and density functional theory studies on tautomerism of 5,5′-diisopropyl-3,3′-bipyrazole in gas phase and solution

To gain a better understanding of the tautomerism of 5,5′-diisopropyl-3,3′-bipyrazole, theoretical studies were performed using the ab initio HF and DFT methods. Several structural and molecular properties, total molecular energies, relative energetic stabilities, tautomeric equilibrium constants, kinetic parameters, Mulliken net charges and pKa values for three tautomers were calculated. Tautomer I presenting a large junction distance between the pyrazolic rings is the most stable. Forms II and III have respectively higher dipole moment and more acidic character.

Molecular structure, spectroscopic (FT-IR and UV-Vis) and DFT quantum-chemical studies on 2-[(2,4-Dimethylphenyl)iminomethyl]-6-methylphenol

Density functional calculations of the structure, vibrational spectra, molecular electrostatic potential and thermodynamic functions have been performed at the B3LYP/6-311++G(d,p) level of theory for the Schiff base compound 2-[(2,4-Dimethylphenyl)iminomethyl]-6-methylphenol. Experimental and theoretical Fourier transform infrared (FT-IR) studies of the title compound show the preference of enol form, as supported by X-ray analysis results. Using the time-dependent density functional theory (TD-DFT) method, electronic absorption spectra of the compound have been predicted and a good agreement is determined with the experimental ones. To investigate the tautomeric stability, optimisation calculations at B3LYP/6-311++G(d,p) level were performed for the enol and keto forms of the title compound. Calculated results show that its enol form is more stable than that of the keto form. The predicted non-linear optical properties of the title compound are much greater than those of urea. The changes in thermodynamic properties for the formation of the title compound with the temperature ranging from 200 K to 500 K have been obtained using the statistical thermodynamic method. At 298.15 K the change of Gibbs free energy for the formation reaction of the title compound is 37.03 kJ/mol. The title compound cannot be spontaneously produced from the isolated monomers at room temperature. The tautomeric equilibrium constant is also computed as 1.23×10−3 at 298.15 K for enol ↔ keto tautomerisation of the title compound.

Ab Initio and Density Functional Theory Study of Keto–Enol Equilibria of Deltic Acid in Gas and Aqueous Solution Phase: A Bimolecular Proton Transfer Mechanism

Keto-enol tautomerism in deltic acid (2,3-dihydroxycycloprop-2-en-1-one) has been studied using ab initio methods and the B3LYP functional of density functional theory, as well as complete basis set (CBS-QB3 and CBS-APNO) and G4 methods. Relative and absolute energies were calculated with each of the methods, whereas computations of geometries and harmonic frequencies for dihydroxycyclopropenone and hydroxycyclopropanedione were computed in the gas phase but were limited to HF, MP2, and the B3LYP functional, in combination with the 6-31++G(3df,3pd) basis set. Using the MP2/6-31++G(3df,3pd) gas phase optimized structure, each species was then optimized fully in aqueous solution by using the polarizable continuum model (PCM) self-consistent reaction field approach, in which HF, MP2, and B3LYP levels of theory were utilized, with the same 6-31++G(3df,3pd) basis set. In both gas and aqueous solution phases, the keto form is higher in energy for all of the model chemistries considered. From the B3LYP/6-31++G(3df,3pd) Gibbs free energy, the keto-enol tautomeric equilibrium constant for 2,3-dihydroxycycloprop-2-en-1-one/3-hydroxy-1,2-cyclopropanedione is computed to be K(T)(gas) = 2.768 × 10(-12) and K(T)(aq) = 5.469 × 10(-14). It is concluded that the enol form is overwhelmingly predominant in both environments.

Computational study of tautomerism and aromaticity in mono- and dithio-substituted tropolone

Keto-enol tautomerism in mono- and dithio-substituted analogs of tropolone was investigated using electronic structure computations. Seven structural isomers of C7H6OS and four of C7H6S2 were optimized fully in gas phase at HF and B3LYP theoretical levels in combination with the 6-311++g** basis set, as well as with the CBS-QB3 and G3 methods. To examine the effects of an aqueous solvent on tautomeric equilibrium constants, each species was optimized in water using the self-consistent reaction field polarizable continuum model at HF/6-311++g** and B3LYP/6-311++g** model chemistries. In both phases it was found that the enol forms were significantly more stable with respect to electronic energy and Gibbs free energy compared to the keto isomers, and outnumbered the keto species by several orders of magnitude. This was understood on the basis of elementary Hückel theory and the 4n + 2 rule, and supported by nucleus independent chemical shifts computations of NMR chemical shifts in these seven membered cyclic systems. © 2012 Wiley Periodicals, Inc.

Density Functional Theory Study of Hypoxanthine Tautomerism in Both the Isolated State and a Modeled-Ideal Aqueous Solution at Several Heterocyclic Protonation Levels

In order to advance the knowledge of prototropic tautomerism from the physicochemical point of view, the purine derivative hypoxanthine has been selected and studied. The overall purpose has been to explore thermodynamic aspects of the heterocycle tautomerism under the influence of both its protonation level and the surrounding dielectric constant. A Density Functional Theory study (at the B3LYP/6-31++G** level) was performed, in which the energetic and thermodynamic stabilities, the electric dipole moment values, the tautomeric equilibrium constants and the tautomeric populations were obtained for several hypoxanthine tautomers under systematically modified heterocyclic protonation levels, considering both isolated and ideal aqueous solution states. Among the interesting results obtained are changes in the tautomeric populations for several heterocyclic protonation states and with the increase of the dielectric constant. Several of the predictions made for an aqueous solution show good agreement with recently reported experimental conclusions. Also, the ionizable groups that contribute to the different hypoxanthine ionization steps in the main tautomers have been established. These and other related results are presented and discussed. Finally, the confidence developed in the predicted tautomeric populations in a modeled-ideal aqueous solution allows us to propose that the methodology applied here can be used for the study of prototropic tautomerism in heterocycles belonging to this class, particularly when the experimental work is challenging in both performance and physicochemical data analysis.

Ab initio studies on acidity and tautomeric equilibrium constants of some benzoxa-, benzothia-, benzoselena-zolinone derivatives

This paper presents ab initio procedure to calculate aqueous-phase acid dissociation constants (pKa) values, accurately. In this work, dissociation and tautomeric equilibrium constants (KT) of some benzoxa-, benzothia-, benzoselena-zolinone derivatives were studied theoretically. For this purpose, Gibbs free energy values for neutral and deprotonated forms of investigated compounds were calculated at gas and aqueous phase by using Hartree–Fock (HF) and density functional theory (DFT) calculation methods. For both calculation methods it was found that 6-311G(d) basis set is the most convenient method. Solvent effects are taken into account by means of conductor-like polarizable continuum model (CPCM). It was shown that, theoretically calculated pKa values are in good agreement with the existing experimental pKa values, which are determined from capillary electrophoresis, potentiometric titration and UV–visible spectrophotometric measurements. Calculated pKa values also revealed that the DFT method (R2=0.92) gave much closed results to experimental values in comparison to Hartree–Fock method (R2=0.86). Due to the all investigated compounds have keto-enol tautomerism, KT and pKT values were calculated without need to form model compounds. Theoretically calculated KT values indicated that, keto forms are predominant for all the investigated compounds.

Limiting Values of the 15N Chemical Shift of the Imidazole Ring of Histidine at High pH

Tautomeric identification by direct observation of (15)N chemical shifts of the imidazole ring of histidine (His) has become a common practice in NMR spectroscopy. However, such applications require knowledge of the "canonical" limiting values of the (15)N chemical shift of the imidazole ring of His in which each form of His, namely, the protonated (H(+)) and the tautomeric N(ε2)-H and N(δ1)-H forms, respectively, is present to the extent of 100%. So far, the adopted canonical limiting values of the (15)N chemical shift have been those available from model compounds. Whether these canonical values reflect those of the individual pure forms of His is investigated here by carrying out an analysis of the second-order shielding differences, ΔΔ = |Δ(ε) - Δ(δ) |, with Δ(ξ) (ξ = ε or δ) being the density functional theory (DFT)-computed average shielding differences between the two nitrogens of the imidazole ring of His in each pure tautomeric form. In the high-pH limit, the results indicate that (i) the ΔΔ values from the DFT-computed shielding, but not from the commonly used canonical limiting values, are in closer agreement with those obtained with experimental chemical shift data from model compounds in solution and solid-state NMR; and (ii) the commonly used canonical limiting values of the (15)N chemical shifts lead to an average tautomeric equilibrium constant that differs by a factor of ∼2.6 from the one computed by using DFT-based (15)N limiting values, raising concern about the practice of using canonical limiting (15)N values. This can be avoided by reporting tautomeric equilibrium constants computed by using only limiting (15)N values for the N(ε2)-H tautomer.

Crystal Structure, Spectroscopy, and Quantum Chemical Studies of (E)-2-[(2-Chlorophenyl)iminomethyl]-4-trifluoromethoxyphenol

The Schiff base compound (E)-2-[(2-chlorophenyl)iminomethyl]-4-trifluoromethoxyphenol has been synthesized and characterized by IR, UV-vis, and X-ray single-crystal determination. The molecular geometry from X-ray experiment in the ground state has been compared using the density functional theory (DFT) with the 6-311++G(d,p) basis set. The calculated results show that the DFT can well reproduce the structure of the title compound. Using the TD-DFT method, electronic absorption spectra of the title compound have been predicted, and a good agreement is determined with the experimental ones. To investigate the tautomeric stability, optimization calculations at the B3LYP/6-311++G(d,p) level were performed for the enol and keto forms of the title compound. Calculated results reveal that its enol form is more stable than its keto form. The predicted nonlinear optical properties of the title compound are much greater than those of urea. The changes of thermodynamic properties for the formation of the title compound with the temperature ranging from 200 to 500 K have been obtained using the statistical thermodynamic method. At 298.15 K, the change of Gibbs free energy for the formation reaction of the title compound is -824.841 kJ/mol. The title compound can spontaneously be produced from the isolated monomers at room temperature. The tautomeric equilibrium constant is also computed as 3.85 × 10(-4) at 298.15 K for enol↔keto tautomerization of the title compound. In addition, a molecular electrostatic potential map of the title compound was performed using the B3LYP/6-311++G(d,p) method.

Manifestation of enol–enol tautomerism in IR spectra of 2-acetylcyclopentanone-d1

IR spectroscopy was used to show that 2-acetylcyclopentanone (2-ACPN) exists in solutions of aprotic organic solvents as a mixture of three tautomeric forms. Assignments of absorption bands in IR spectra of 2-ACPN and its deuterated analog 2-ACPN-d1 were made based on calculations of normal mode frequencies by a B3LYP/6-311++(2 d,2p) method for the gas phase and taking into account the influence of aprotic solvents in the framework of a polarizable continuum model (PCM). The enol–enol tautomeric equilibrium constant was evaluated for 2-ACPN-d1 in solutions of the aprotic solvents. The content of the diketo form of 2-ACPN was shown to depend strongly on the solvent polarity and increased with it.

Density functional computational studies on 2‐[(2,4‐Dimethylphenyl)iminomethyl]‐3,5‐dimethoxyphenol

AbstractDensity functional calculations of the structure, molecular electrostatic potential, and thermodynamic functions have been performed at B3LYP/6‐31G(d) level of theory for the title compound of 2‐[(2,4‐dimethylphenyl)iminomethyl]‐3,5‐dimethoxyphenol (I). To investigate the tautomeric stability, optimization calculations at B3LYP/6‐31G(d) level were performed for the enol and keto forms of I. Calculated results reveal that the enol form of I is more stable than its keto form. The predicted nonlinear optical properties of I are much greater than ones of urea. The changes of thermodynamic properties for the formation of the title compound with the temperature ranging from 200 to 500 K have been obtained using the statistical thermodynamic method. At 298.15 K, the change of Gibbs free energy for the formation reaction of I is 32.973 kJ/mol. The title compound can not be spontaneously produced from the isolated monomers at room temperature. The tautomeric equilibrium constant is computed as 0.868 at 298.15 K for enol‐imine↔keto‐amine tautomerization of I. In addition, natural bond orbital analysis of I was performed using the B3LYP/6‐31G(d) method. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012

Density functional modelling studies on N-2-Methoxyphenyl-2-oxo-5-nitro-1-benzylidenemethylamine

Density functional calculations of the structure, molecular electrostatic potential and thermodynamic functions have been performed at B3LYP/6-31G(d) level of theory for the title compound of N-2-Methoxyphenyl-2-oxo-5-nitro-1-benzylidenemethylamine. To investigate the tautomeric stability, optimization calculations at B3LYP/6-31G(d) level were performed for the enol and keto forms of the title compound. Calculated results reveal that the enol form of the title compound is more stable than its keto form. The predicted non-linear optical properties of the title compound are much greater than ones of p-Nitroaniline. The changes of thermodynamic properties from the monomers to title compound with the temperature ranging from 200 K to 450 K have been obtained using the statistical thermodynamic method. At 298.15 K the change of Gibbs free energy for the formation reaction of the title compound is 30.654 kJ/mol. The title compound cannot be spontaneously produced from the isolated monomers at room temperature. The tautomeric equilibrium constant is computed as 0.0192 at 298.15 K for enol-imine ↔ keto-amine tautomerization of the title compound. In addition, natural bond orbital analysis of the title compound were performed using the B3LYP/6-31G(d) method.