Kinetic and thermodynamic study of inter‐ and intramolecular proton transfer in N′‐acetyl formohydrazide tautomers

Nine tautomers and eleven possible tautomeric interconversions of N′‐acetyl formohydrazide have been studied at B3LYP/6‐311++G** level of theory. From these calculations, optimized geometries, molecular parameters, IR frequencies, NMR chemical shifts, and energetic results are obtained. In all tautomers except tautomers 4, E isomer is more stable than Z isomer. Energetic data were used to calculate the energy barriers of tautomeric interconversions and very high energy barriers were obtained for all tautomeric interconversions. Moreover, study of solvent effects on relative stabilities of tautomers and transition states showed that they are similar to those in the gas phase. In addition, intermolecular proton transfer with the assistance of one to three water molecules has been studied and the results showed that activation barriers in water‐assisted tautomerism are in general lower than those in the gas phase. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

DFT investigation on the intramolecular and intermolecular proton transfer processes in 2-aminobenzothiazole (ABT) in the gas phase and in different solvents

DFT at the B3LYP/6-311++G(d,p) level of theory was performed to geometrically, thermodynamically, and kinetically investigate the tautomerism process of 2-aminobenzothiazole (ABT) with n water molecules (n = 1–3) and without water in the gas phase and in different solvents with a gradual increase in their dielectric constants. The geometries of the envisaged tautomers were optimized in the gas phase and in solution with the polarized continuum model (PCM). Equilibrium and rate constants for the forward and reverse intra-/intermolecular isolated and water-assisted tautomerism reactions were also calculated. The results suggest that the activation energy of the transition state of direct proton transfer in the isolated reaction is very high and that the rate constant is very slow (~ 10^?24 s), reflecting that the reaction is thermodynamically unfavored, whereas the barrier differences between the transition states of the tautomers decrease gradually as the number of water molecules increases from one to three. Moreover, the rate constants of the proposed reactions are ~ 10²³–10²⁵ faster than those of the isolated reaction, and the water-assisted tautomerism paths can be performed quickly, especially with the assistance of two molecules of water.

     

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.     

DFT and MP2 study of isomery scheme in Formazan and intermolecular and intramolecular proton transfer between its tautomers

DFT and Moller Plesset (MP2) calculations were applied to study of isomery scheme in formazan. Formazan that can be presented by three tautomers and eight isomers has various applications in dyes, complexes, and biochemistry. The structures of its isomers and related transition states were optimized, and important molecular parameters, IR frequencies, and energetic results were extracted. The relative stabilities of formazan isomers in the gas phase were found to be as 1EZ >1ZZ >1EE >1ZE >2EE > 3 >2EZ >2ZZ >TS1 >TS3 >TS2. Thermodynamic data confirms that tautomer 1 is major tautomer, and all possible tautomerism interconversions have small rates at room temperature. Then, relative stabilities were calculated in different solvents (chloroform, tetrahydrofuran, acetone, and water). The relative stabilities and thermodynamic data in solvents are nearly similar to those in the gas phase, but the rate constants are slightly more than that in the gas phase. Moreover, relative stabilities of formazan isomers and intermolecular proton transfer in presence of one to three molecules of water have been studied. The results showed that activation barriers in water‐assisted tautomerisms are in general lower than those in the gas phase, but the relative energies of isomers do not change importantly by water clusters. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012     

QM study on regioselectivity in the synthesis of pyrimido[4,5-b][1,4]benzothiazines: kinetic and thermodynamic point of view

In the present study, the experimentally observed regioselectivity in pyrimido[4,5-b][1,4]benzothiazine synthesis has been modeled using density functional theory method at M06/6-311++G** level. Also the tautomerism of all four tautomers of 6-ethyl-2-thio(1H) pyrimidin-(3H)-4-one as an important intermediate through the reaction path in pyrimido[4,5-b][1,4]benzothiazine synthesis has been investigated extensively in the gas and solution phase. The stability order of tautomers was found as A > D > B > C, in gas and chloroform solvent; however, changing to more polar solvents this order was changed as A > B > D > C using polarized continuum model. In the next step, we focused on another significant feature of this synthesis which has major role in the observed regioselectivity. Two proposed reaction paths with two different transition states that it seems the mode of its intermolecular cyclization has a special role in regioselectivity of the final product have been considered. Comparison of our calculated NMR and IR spectrum with those already reported for some pyrimido[4,5-b][1,4]benzothiazines demonstrates a reliable agreement. Moreover, all obtained results in the gas and solution phase confirm that the synthesis of above-mentioned compound is thermodynamically more favorable than the possible regioisomeric product.     

DFT study on the isomerization in vitamin B6

Isomerization and tautomerism reactions of the active form of vitamin B6, pyridoxal phosphate, are studied at B3LYP level of theory using 6-311++G(2df,p) basis set in gas and aqueous phases. Twenty-three transition state (TS) structures for vitamin B6 isomerization are optimized, including 13 TS structures for O–H and C–C rotations, 8 TS structures for imine–enamine tautomerism, and 2 TS structures for keto–enol tautomerism. Activation energy (E _a), imaginary frequency (υ), and Gibbs free energy of activation (ΔG ^#) for the isomerization reactions are calculated. The activation energies of the imine–enamine tautomerism are in the range of 190–280 kJ/mol and of O–H and C–C rotations are mainly less than 60 kJ/mol. Also, our calculation shows that the imine forms of B6 are mainly more stable than the enamine forms. Effect of microhydration on the TS structures and activation energies is also investigated. It is found that the presence of water molecules catalyzes only the imine–enamine tautomerism.     

An ab initio study of water clusters in gas phase and bulk aqueous media: (H2O)n,n=1–12

Geometries of several clusters of water molecules including single minimum energy structures of n‐mers (n=1–5), several hexamers and two structures of each of heptamer to decamer derived from hexamer cage and hexamer prism were optimized. One structural form of each of 11‐mer and 12‐mer were also studied. The geometry optimization calculations were performed at the RHF/6‐311G* level for all the cases and at the MP2/6‐311++G** level for some selected cases. The optimized cluster geometries were used to calculate total energies of the clusters in gas phase employing the B3LYP density functional method and the 6‐311G* basis set. Frequency analysis was carried out in all the cases to ensure that the optimized geometries corresponded to total energy minima. Zero‐point and thermal free energy corrections were applied for comparison of energies of certain hexamers. The optimized cluster geometries were used to solvate the clusters in bulk water using the polarized continuum model (PCM) of the self‐consistent reaction field (SCRF) theory, the 6‐311G* basis set, and the B3LYP density functional method. For the cases for which MP2/6‐311++G** geometry optimization was performed, solvation calculations in water were also carried out using the B3LYP density functional method, the 6‐311++G** basis set, and the PCM model of SCRF theory, besides the corresponding gas‐phase calculations. It is found that the cage form of water hexamer cluster is most stable in gas phase among the different hexamers, which is in agreement with the earlier theoretical and experimental results. Further, use of a newly defined relative population index (RPI) in terms of successive total energy differences per water molecule for different cluster sizes suggests that stabilities of trimers, hexamers, and nonamers in gas phase and those of hexamers and nonamers in bulk water would be favored while those of pentamer and decamer in both the phases would be relatively disfavored. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 81: 90–104, 2001     

2-羟基咪唑在气相和水中的异构平衡和质子迁移的从头算计算和Monte Carlo模拟

采用从头算方法在MP2/6-31＋G^*水平上研究了2-羟基咪唑分子在孤立分子和一水合物的异构体的相对稳定性和可能的质子迁移反应, 分析了一个水分子的参与对2-羟基咪唑分子异构体的相对稳定性和质子迁移速率的影响, 采用Monte Carlo模拟方法研究了反应体系在水溶液中反应的溶剂化效应. 结果表明: 2-羟基咪唑分子的孤立分子和一水合物的最稳定异构体相同, 都为酮式. 直接质子迁移反应在水溶液中活化能垒有轻微增加, 但产物能量得到降低; 水助催化质子迁移反应在水溶液中的活化能垒和产物能量都得到明显降低. 综合气相和水相的计算结果, 2-羟基咪唑水助催化的质子迁移反应较易进行, 且在水溶液中进行容易, 可以很容易被实验观察到.     

Theoretical studies on the chemical decomposition of 5-aza-2′-deoxycytidine: DFT study and Monte Carlo simulation

The decomposition mechanism of 5-Aza-2′-deoxycytidine has been studied by the use of computational techniques. Optimized structures for all of the stationary points in the gas phase were investigated at B3LYP/6-31+G(d,p) level of theory. Single-point energies were determined employing the ab initio MP2 method in conjunction with the 6-311++G(d,p) basis set. Five possible pathways, paths 1–5, were evaluated. In each pathway, the direct (A-paths 1–5) and water-assisted (B-paths 1–5) processes were considered. Meanwhile, the local microhydration model with the direct participation of three water molecules around the reaction centers was adopted to mimic the system for the water-assisted decomposition mechanisms above, where one water molecule is the nucleophilic reactant and the other two are the auxiliary molecules located on each side of the nucleophilic water. The results in the gas phase exhibit that the energy barriers of the water-assisted pathways based on the local microhydration model decrease dramatically by about 15–20 kcal/mol as compared with those of the direct pathways because of the contribution of the auxiliary water molecules. In addition, bulk solvent effects of water were determined by means of the self-consistent reaction field based on the conductor-like polarized continuum model and Monte Carlo simulation with free energy perturbation (MC-FEP) technique, respectively. Our computational results indicate that B-path 3 in the decomposition reaction of 5-azadC is the most favorable, where the calculated rate constant (1.68 × 10⁻³ min⁻¹) using the MC-FEP method is within the range of the experimentally determined values [(5.89 ± 0.54) × 10⁻³ min⁻¹ by UV and (1.46 ± 0.08) × 10⁻³ min⁻¹ by NMR].     

Electronegativity and resonance parameters from the geometry of monosubstituted benzene rings

Reference values of the structural substituent parameters, S _E and S _R, measuring the electronegativity and resonance effects, respectively, of functional groups (Campanelli et al. J Phys Chem A 107:6429–6440, 2003) have been determined from the benzene ring geometries of 100 Ph–X species, including different conformations of the same molecule. Geometries have been obtained by quantum chemical calculations at the HF/6-31G*, HF/6-311++G**, and B3LYP/6-311++G** levels of theory. The substituent parameters from HF/6-311++G** calculations are in close agreement with those determined at the HF/6-31G* level. Using the B3LYP density functional yields S _E and S _R values which—in general—correlate well with the corresponding HF values. Exceptions occur with some charged groups, and, in the case of S _E, with a few dipolar groups having very high or low electronegativities. S _R values from B3LYP calculations are about 22% smaller than the corresponding HF values. The variations of the benzene ring geometry caused by electronegativity, resonance, and steric effects are illustrated in some detail.     

X-ray,tautomeric preference,vibrational spectra,and density functional studies on benzoxazole and benzoxazoline derivatives

The solid-state X-ray diffraction, FT-IR, and FT-Raman measurements have been performed on bis(benzoxazole-2-ylthio)methane. Molecular structures and normal vibrations of bis(benzoxazole-2-ylthio)methane have been compared with those of its fragments in thiolic (2-mercaptobenzoxazole and 2-methylthiobenzoxazole) and thionic (benzoxazoline-2-thione and 3-methyl-benzoxazoline-2-thione) forms to elucidate substitutional effects. The observed IR and Raman bands of these molecules have been assigned in the frameworks of calculated mode frequencies as well as the calculated IR and Raman intensities at the B3LYP/6-311++G** level in gas phase. The assignments of all fundamental bands have been expressed in terms of internal coordinates and their percent potential energy distributions. The thionic tautomers are significantly more stable than the thiolic tautomers (by more than 5 kcal/mol) with a keto-enol transition state that lies more than 40 kcal/mol above the most stable thionic tautomers. Therefore, the thionic tautomers are the main species at room temperature. Despite the huge transition barrier, the thiolic tautomers can also exist according to the detailed vibrational spectral analyses. Potential energy surface scans find that the thiolic tautomers have two stable conformations due to the orientation of their SH and SCH₃ moieties.     

Stereoelectronic structure of α-bromoalkenyl trifluoromethyl ketones

The results of quantum-chemical calculations at the B3LYP/6-311G** level of theory showed that (Z)-α-bromo-β-arylalkenyl trifluoromethyl ketones are more stable than the corresponding E isomers by 4–5 kcal/mol. Relatively large positive charge on the olefinic β-carbon atom and strong polarization of the C=C bond in both Z-s-cis and Z-s-trans conformers makes bromoalkenyl trifluoromethyl ketones the most potent Michael acceptors among α,β-unsaturated carbonyl compounds. The calculated data are very consistent with the experimental IR spectra.     

Solvent-assisted intramolecular proton transfer in thiopurinol: application of M06-2X functional

All available conformers of tisopurine as an important pharmaceutical molecule are optimized and frequency calculations calculated at M06-2X/6-311++G(2d,2p) level of theory. These conformers are classified in 22 different tautomers, tautomer Z showing the most stable tautomer in the gas phase. Effects of four different solvents on the most stable conformer of each tautomer is calculated. Solvents cause stabilization of all conformers and relative solvent stabilization is as follows: water > DMSO > acetone > toluene. Energy profile for such stabilization is illustrated and mechanism of proton transfer studied at the same level of theory. Solvent-assisted proton transfer performed when water and methanol used as solvents. Results indicate that explicit solvent effect has much more stabilization on tautomerization processes compared to implicit solvent effect.     

Theoretical Study of Molecular Structure, Tautomerism, and Geometrical Isomerism of N-Methyl- and N-Phenyl-Substituted Cyclic Imidazolines, Oxazolines, and Thiazolines

The geometries of various tautomers and isomers of 2-methylamino-2-imidazoline, 2-methylamino-2-oxazoline, 2-methylamino-2-thiazoline, 2-phenylamino-2-imidazoline, 2-phenylamino-2-oxazoline, and 2-phenylamino-2-thiazoline have been studied using the Becke3LYP/6–31+G(d,p) DFT, ONIOM(Becke3LYP/6–31+G(d,p):HF/3–21G^*) and ONIOM(Becke3LYP/6–31+G(d,p):AM1) methods. The optimized geometries indicate that these molecules show a distinctly nonplanar configuration of the cyclic moieties. In the gas phase, the amino tautomers (with exception of 2-phenylamino-2-imidazoline) are computed to be more stable than the imino tautomers. Of the two possible (E and Z) isomers of methyl and phenyl derivatives of imino-oxazolidine and imino-thiazolidine species, the (Z) isomers have the lowest energy. The iminozation free energies in the gas phase were found to be 5 – 15 kJ/mol. Absolute values of K _T depend strongly on the accuracy of the method used for calculation of free energy. Solvation (using the MD simulations) causes, in most cases, a shift in tautomeric preference toward the imino species.     

Electron ionization mass spectra and tautomerism of substituted 2‐phenacylquinolines

Tautomerism has been studied conventionally in solutions or in the solid state. However, the importance of mass spectrometry in the gas phase was realized relatively late. 2‐Phenacylquinolines are known to undergo ketimine‐enaminone tautomerism. The ratio of tautomers is dependent on the nature of the phenyl ring substituent and the Hammett substituent constants σ. Theoretical calculations indicate the presence of ketimine and enaminone tautomers in the gas phase. The electron ionization mass spectra of eight 2‐phenacylquinolines (ketimine form) were recorded at 70 eV in order to determine the fragmentation routes and to screen for the presence of their enaminone tautomers, (Z)‐2‐benzoylmethylene‐1,2‐dihydroquinolines, in the gas phase. The relative abundances or total ion currents of some ions correlated with the Hammett substituent constants and Hammett‐Brown constants. The product ions [M–CO]^{+ .} and [M–HCO]⁺ were observed. A reaction mechanism is suggested for the formation of these ions, requiring skeletal rearrangements. The results furnish information relating to tautomerism in the gas phase. Copyright © 2009 John Wiley & Sons, Ltd.     

Theoretical study on keto–enol tautomerism and isomerization in pyruvic acid

Isomerization and tautomerism of 12 isomers of pyruvic acid including 4 keto and 8 enol forms were studied at the MP2 and B3LYP levels of theory using 6‐311++G(2df,p) basis set, separately. Activation energy (E_a), imaginary frequency (υ), and Gibbs free energy (ΔG^#) of the considered isomerization and tautomerism reactions were calculated. Interconversion of the enol forms proceeds through two paths: (i) proton transfer and (ii) internal rotation. Activation energies for the proton transfer paths were in the range of 125–145 kJ/mol and for the internal rotation paths were in the range of 5–45 kJ/mol. Keto–enol tautomerism of pyruvic acid proceeds only through proton transfer route and their activation energies were in the range of 200–300 kJ/mol. Effect of microhydration on the transition state structures and activation energies was also investigated. It was found that the presence of a water molecule catalyzes the isomerization and tautomerism reactions of pyruvic acid so that the activation energies decrease. © 2013 Wiley Periodicals, Inc.     

Quantum chemical and experimental studies on the structure and vibrational spectra of substituted 2-pyranones

A systematic study on the structural characteristics of the 2-pyranone ring containing molecules with bromine, nitrile, and amide substituents at the C-3 position in the ring is conducted in the electronic ground (S ₀) state by DFT calculations using the B3LYP/6-311++G** method. The geometrical structure of the bromine substituted compound, which shows potent hepatoprotective activity, is studied both in the ground (S ₀) and first excited singlet (S ₁) states using RHF/6-311++G** and CIS/6-311++G** methods respectively. The molecules are found to exist in two isomeric forms gauche and trans that have the enthalpy difference of less than 3.32 kcal/mol; the latter is the preferred orientation in the gaseous phase. The S ₁ state is a ¹(π,π*) state that arises π-electron transfer from the region of a double bond in the pyranone ring to the region of the internuclear bond connecting the 2-pyranone and benzene rings. A complete vibrational analysis is conducted for the 3-bromo-6-(4-chlorophenyl)-4-thiomethyl-2H-pyran-2-one molecule based on the experimental infrared spectra in the 50–4000 cm⁻¹ region and DFT/6- 311++G** computations of vibrational frequencies for the gauche and trans isomeric forms. Spectral assignments based on the potential energy distribution along the internal coordinates confirm the nonplanar structure of the molecule.     

尿嘧啶水助质子转移反应机理的研究

用密度泛函理论,在B3LYP/6-311++G**计算水平下分别对尿嘧啶所有的气相、液相、过渡态和质子转移异构体的结构进行全优化,获得它们在气相和水相中的几何结构和电子结构,PGM反应场溶剂模型用于水相计算.结果显示:在气相和水相中,水参与反应降低了互变异构质子迁移的反应活化能,对互变异构质子迁移的反应起到催化作用,但...     

密度泛函方法研究气相胞嘧啶的互变异构化

By comparing the ready experimental results with the calculated results obtained at 7 basis sets and 3 theoretical levels, respectively, for the tautomeric form Cyt1 of cytosine, the relatively accurate B3LYP/6-311+G** theoretical method to study the tautomerism of cytosine was chosen. The ground-state structures of 8 tautomers of cytosine were fully optimized at B3LYP/6-311+G** level, and the tautomerism of 6 relatively stable tautomers of cytosine was studied. The frequency analysis was performed on all the optimized structures. For the ground state geometries, all the calculated frequencies are real; for the transition-state geometries, there is only one imaginary frequency for each structure. Detailed Intrinsic Reaction Coordination calculations were carried out to guarantee the optimized transition-state structures being connected to the related tautomers. All the energies given include the zero-point energy corrections. The theoretical results can give a reasonable interpretation for the experimental results.     

Hydration effect on the stability of the keto-enol tautomers of 5-hydroxy-6-methyluracil

The structure and energies of six tautomeric forms of 5-hydroxy-6-methyluracil (OMU) and their 1:n (n = 1−4) complexes with water were determined by the density functional theory (PBE/3z) method. The stability series of the tautomers and changes in it depending on the number of water molecules in the nearest environment of the tautomer were found. The effect of the water solvent was also included using the continuum (B3LYP/6-311+G(2d,p), COSMO) model. Both complex formation and medium effects significantly influenced the stability series of the tautomers. Although the decrease in the energy of the diketo form on hydration was smaller than for the enol states, diketo tautomer a remained the most stable form of OMU in solution. Inclusion of hydration in calculations suggests that the energies of three enol tautomers b–d were equalized (ΔH ≈ 5.5 kJ/mol). This should be taken into account for the conditions that facilitate the keto-enol tautomerism of OMU.