DFT and MP2 study of simple and water-assisted tautomerism in amidrazones

DFT and MP2 methods were used to calculate structural parameters, vibrational modes, solvent effect, and energetic properties of amidrazones. Amidrazones can be presented by three tautomeric forms and six isomers. All tautomers and transition states were optimized at the B3LYP/6-311++g** and MP2/6-311++G** levels of theory. The relative stabilities of amidrazone isomers in the gas phase were found to be as 1Z > 1E > 2E > 2Z > 3E > 3Z > TS(1–2) > TS(1–3). The calculated energy differences between E and Z isomers are very low and between different tautomers are nearly low, but the energy barriers for tautomerism interconversions at the gas phase are high. The kinetic and thermodynamic data in solvents (chloroform, tetrahydrofuran, acetone, and water) are nearly similar to those in the gas phase but their rate constants are slightly less than those in the gas phase. Moreover, equilibrium and rate constants of intermolecular tautomerism in presence of 1–3 molecules of water were calculated. Computed energy barriers show that the barrier energy of water-assisted tautomerism is very lower than that in simple tautomerism and also calculated binding energies show that water can stabilize transition states more than tautomers. Therefore, this water-assisted tautomerism can be performed fast, especially with the assistance of two molecules of water.     

Rare Tautomers of 1‐Methyluracil and 1‐Methylthymine: Tuning Relative Stabilities through Coordination to PtII Complexes

We have computationally explored how the relative stabilities of 1‐methyluracil (1‐MeUH) tautomers can be tuned through coordination of these tautomers to Pt^II complexes with a particular set of ligands. This has been done using density functional theory at the BP86/TZ2P level. Thus, we have examined the water/1‐MeUH exchange reactions of [Pt^II(A)(B)(C)(OH₂)]^q + 1‐MeUH to uncover: i) which tautomers are best stabilized by the Pt^II complex, and ii) how the net charge q in the complex affects the reaction energy. The net charge q depends on the ligands A, B, and C, which can be the neutral NH₃ or anionic Cl^?. To reveal the effect of solvation, all reaction systems are studied both in the gas phase and in water. Also the stabilization of tautomers of 1‐methylthymine (1‐MeTH) by cisplatin is investigated. The calculations reveal that relative energies of the metal (here: Pt^II)‐complexed forms of the various tautomers (here: of 1‐MeUH and 1‐MeTH) do not parallel those of the free tautomers. Rather, a rare nucleobase tautomer, despite its low natural abundance, may become favored over the predominant one when complexed to a metal ion.     

The Substituent Effect on the Energy Profiles of Inter and Intramolecular Proton Transfers between Phosphine Oxide‐Phosphinous Acid Tautomers

This report presents the energy details related to mechanistic pathways of tautomeric interconversion between phosphinous acids and phosphine oxides with different substituents using DFT, MP2 and CCSD (T) calculations. Four mechanisms consisting of simple, dimer, water‐assisted (with 1, 2, and 3 molecules of water), and methanol‐assisted have been considered. In the most cases and all pathways, the halogen‐containing phosphorus compounds preferred phosphinous acid tautomer and the other structures preferred phosphine oxide tautomers. In simple tautomerism, the high‐energy barriers showed the impossible pathway for this interconversion and halogen substituents had higher rate constants. In dimeric mechanism, the relative stability of phosphine oxide tautomer was increased and the tautomeric processes via this mechanism were found to have the higher rates versus the simple mechanism. In the solvent‐assisted mechanism, except one structure, the relative stability of phosphinous acids was increased in comparison with the simple or dimer cases. Moreover, activation energies showed the great enhancements in the rates of these interconversions in the direct presence of the solvent.     

Prototropic tautomers of 5‐methylcytosine and enthalpy changes of their protonation,deprotonation, and deamination: Hybrid density functional B3LYP study

Molecular and thermodynamic properties such as geometric parameters, dipole moments, vibrational frequencies, the first ionization potentials, relative tautomerization energies, and tautomeric equilibrium constants of all prototropic tautomers of 5‐methylcytosine have been studied at the hybrid density functional level B3LYP/6‐31+G(d,p). The methylation on the C5 atom does not lead to significant geometric deformation of the pyrimidine structures of the corresponding tautomers of cytosine, which maintains the similar stability order. The tautomeric species 2‐oxo‐4‐amino [T(0)], 2‐hydroxy‐4‐amino [T(1‐2s) and T(1‐2t)], and trans‐2‐oxo‐4‐imino [T(3‐4t)] are predominated in the gas phase. The zwitterionic conformers of tautomerism [T(1‐4)] and protonation [P(4), P(1‐2s‐4), P(1‐2t‐4), and P(1‐3‐4)] are investigated for the first time due to their close relationship with deamination during genetic repair. Enthalpy changes (Δ_rH) of protonation, deprotonation, and deamination are calculated for these tautomeric species at room temperature; it is noted that the relative enthalpies [δ(ΔH)] of the tautomers are rationalized well in terms of a second‐order polynomial of the sum of the mean Δ_rH values of protonation and deprotonation processes. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002     

Theoretical investigation of solvent effects on tautomeric equilibrium of 2‐diazo‐4,6‐dinitrophenol

The density functional theory has been used to study the tautomeric equilibrium of 2‐diazo‐4,6‐dinitrophenol(DDNP) in the gas phase and in 14 solvents at the B3LYP/6‐31G* level. The solvent effects on the tautomeric equilibria were investigated by the self‐consistent reaction field theory (SCRF) based on conductor polarized continuum model (CPCM) in apolar and polar solvents and by the hybrid continuum‐discrete model in protic solvent, respectively. Solvent effects on the computed molecular properties, such as molecular geometries, dipole moments, E_LUMO, E_HOMO, total energies for DDNP tautomers and transition state, tautomerization energies and solvation energies have been found to be evident. The tautomeric equilibrium of DDNP is solvent‐dependent to a certain extent. The tautomer I (cyclic azoxy form) is preferred in the gas phase, while in nonpolar solvents tautomer I and II (quinold form) exist in comparable amounts, and in highly polar solvents, the tautomeric equilibrium is shifted in favor of the more polar tautomer II . © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Computational Study of Proton Transfer in Tautomers of 3‐ and 5‐Hydroxypyrazole Assisted by Water

The tautomerism of 3‐ and 5‐hydroxypyrazole is studied at the B3LYP, CCSD and G3B3 computational levels, including the gas phase, PCM–water effects, and proton transfer assisted by water molecules. To understand the propensity of tautomerization, hydrogen‐bond acidity and basicity of neutral species is approached by means of correlations between donor/acceptor ability and H‐bond interaction energies. Tautomerism processes are highly dependent on the solvent environment, and a significant reduction of the transition barriers upon solvation is seen. In addition, the inclusion of a single water molecule to assist proton transfer decreases the barriers between tautomers. Although the second water molecule further reduces those barriers, its effect is less appreciable than the first one. Neutral species present more stable minima than anionic and cationic species, but relatively similar transition barriers to anionic tautomers.     

5-氟胞嘧啶互变异构的密度泛函理论计算

采用BH-HLYP/6-311＋G**方法对10种气相和水相中可能存在的5-氟胞嘧啶互变异构体进行了几何全优化, 并计算出它们的总能量和吉布斯自由能. Onsager反应场溶剂模型用于水相的计算. 计算结果表明, 5-氟胞嘧啶在气相中主要以烯醇式-氨基式形式存在, 在水相中主要以酮式-氨基式形式存在. 溶剂化自由能与异构体的气相偶极矩存在相关性．进一步求得互变异构化以及构象异构化和顺反异构化的过渡态, 探讨异构化过程中的几何结构和能量的变化.     

Synthesis of New Isoxazolo[4,5‐d]pyrimidines as Antitumor Agents

The present paper (publication) concerns the synthesis of new isoxazole[4,5‐d]pyrimidine derivatives. There are only a few publications in the chemical literature that report the derivatives of the [4,5‐d] isomer. Our new compounds, the derivatives of this isomer, were obtained using a new manner that differs from those reported in the aforementioned publications in that we used the tautomers of 3‐arylo‐4‐imino‐5‐carbethoxy isxazole 3 and 4 as the starting compounds instead of using their 4‐amino forms. Their tautomeric form proved chemically stable, and, as a result of ammonolysis, we obtained the compounds 5 and 6 . The cyclization of the amides of 5 and 6 with various aldehydes yielded new derivatives, 10 – 19 , with good yields. As a by‐product, the 4‐amino tautomer form in by degrees and was reacted also with aldehydes, and we isolated Schiff bases 20 – 25 with low yields. Some of these compounds were tested for their antitumor activity at National Cancer Institute, Bethesda, MD, USA.     

6-巯基嘌呤互变异构体的密度泛函理论计算

在密度泛函B3LYP/6-311G水平下,对8种气相和水相中可能存在的6-巯基嘌呤异构体进行了几何构型的全自由度优化,并计算出它们的总能量、焓、熵、吉布斯自由能．Onsager反应场溶剂模型用于水相的计算．计算结果表明,6-巯基嘌呤在气相和水相中主要以硫酮形式存在．在气相中,硫酮．N(7)(H)要比硫酮-N(9)(H)更稳定,而在水相中,则硫酮-N(9)(H)要比硫酮-N(7)(H)更稳定．计算结果同已有实验结果一致．6-巯基嘌呤的熵效应小,对互变异构平衡几乎没有显著的影响,而焓变对互变异构产生了主要的影响．较详细地讨论了水溶剂化作用对异构体的能量、几何结构、电荷分布和偶极矩的影响,溶剂化吉布斯自由能与异构体的气相偶极矩存在相关性．     

Towards the design of novel boron‐ and nitrogen‐substituted ammonia‐borane and bifunctional arene ruthenium catalysts for hydrogen storage

Electronic‐structure density functional theory calculations have been performed to construct the potential energy surface for H₂ release from ammonia‐borane, with a novel bifunctional cationic ruthenium catalyst based on the sterically bulky β‐diketiminato ligand (Schreiber et al., ACS Catal. 2012, 2, 2505). The focus is on identifying both a suitable substitution pattern for ammonia‐borane optimized for chemical hydrogen storage and allowing for low‐energy dehydrogenation. The interaction of ammonia‐borane, and related substituted ammonia‐boranes, with a bifunctional η⁶‐arene ruthenium catalyst and associated variants is investigated for dehydrogenation. Interestingly, in a number of cases, hydride‐proton transfer from the substituted ammonia‐borane to the catalyst undergoes a barrier‐less process in the gas phase, with rapid formation of hydrogenated catalyst in the gas phase. Amongst the catalysts considered, N,N‐difluoro ammonia‐borane and N‐phenyl ammonia‐borane systems resulted in negative activation energy barriers. However, these types of ammonia‐boranes are inherently thermodynamically unstable and undergo barrierless decay in the gas phase. Apart from N,N‐difluoro ammonia‐borane, the interaction between different types of catalyst and ammonia borane was modeled in the solvent phase, revealing free‐energy barriers slightly higher than those in the gas phase. Amongst the various potential candidate Ru‐complexes screened, few are found to differ in terms of efficiency for the dehydrogenation (rate‐limiting) step. To model dehydrogenation more accurately, a selection of explicit protic solvent molecules was considered, with the goal of lowering energy barriers for H‐H recombination. It was found that primary (1°), 2°, and 3° alcohols are the most suitable to enhance reaction rate. © 2014 Wiley Periodicals, Inc.     

7-硫代鸟嘌呤互变异构体的密度泛函理论计算

在密度泛函B3LYP/6-311G^**水平下,对14种气相和水相中可能存在的7-硫代鸟嘌呤异构体进行了几何构型全自由度优化,并计算出它们的总能量、焓、熵、吉布斯自由能.Onsager反应场溶剂模型用于水相的计算.计算结果表明,7-硫代鸟嘌呤在气相中和水相中主要以硫酮形式存在.在气相中,硫酮-N(6)(H)要比硫酮-N(4)(H)更稳定,而在水相中,则硫酮-N(4)(H)要比硫酮-N(6)(H)更稳定.计算结果同已有实验结果一致.7-硫代鸟嘌呤互变异构的熵效应小,对互变异构平衡没有显著的影响,而焓变对互变异构产生了主要的影响.较详细地讨论了水溶剂化作用对异构体的能量、几何结构、电荷分布和偶极矩的影响.溶剂化自由能与异构体的偶极矩存在相关性.     

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.     

6-硫代黄嘌呤互变异构体的密度泛函理论计算

在密度泛函B3LYP/6-311G**水平下,对14种气相和水相中可能存在的6-硫代黄嘌呤异构体进行了几何构型的全自由度优化,并计算出它们的总能量、焓、熵、吉布斯自由能。Onsager反应场溶剂模型用于水相的计算.计算结果表明,6-硫代黄嘌呤在气相中和水相中主要以硫酮的形式存在.在气相和水相中,硫酮-N7(H)均比硫酮-N9(H)更稳定.计算结果同已有实验结果一致.6-硫代黄嘌呤异构化的熵效应小,对互变异构平衡几乎没有显著的影响,而焓变对互变异构产生了主要的影响.较详细地讨论了水溶剂化作用对异构体的能量、几何结构、电荷分布和偶极矩的影响.     

3‐Hydro­xy‐6‐[(4‐hydroxy­phenyl­amino)­methyl­ene]­cyclo­hexa‐2,4‐dienone and 2‐hydroxy‐6‐[(4‐hydroxy­phenyl­amino)­methyl­ene]­cyclo­hexa‐2,4‐dienone

The title compounds, both C₁₃H₁₁NO₃, exist as the keto–amine tautomers, and the formal hydroxyl H atoms, which display strong intramolecular hydrogen bonds, are located on the N atoms. This is a verification of the preference for the keto–amine tautomeric form in the solid state. The 2‐hydroxy isomer has two independent mol­ecules, with the mol­ecules linked by intramolecular N—H⋯O and O—H⋯O and intermolecular O—H⋯O hydrogen bonds into three‐dimensional networks.     

Tautomeric equilibria of 2‐ and 4‐thiouracil in gas phase and in solvent: A density functional study

The relative stabilities of the five favored tautomers of 2‐ and 4‐thiouracil in gas phase and in water solution were determined by density functional theory employing the Becke, Lee, Yang, and Parr (B3LYP) exchange–correlation potential and the three 6‐31G(d,p), 6‐311++G(d,p), and triple‐zeta valence (TZVP) basis sets. Zero‐point vibrational corrections were also computed. Bulk solvent effects were studied in the framework of the self‐consistent reaction field approach by the polarizable continuum model. All calculations indicate that the most stable tautomer for both species, in the gas phase as well as in solution, has the oxo‐thione form, in full agreement with the previous ab initio and experimental studies. The tautomeric stability orders obtained in the aqueous solution are sensibly different from that in the gas phase. At B3LYP/6‐311++G(d,p) level in the gas phase, the following orders of stability for 2‐ and 4‐thiouracil tautomers were observed, respectively: S2U1>S2U2>S2U4>S2U5>S2U3 and S4U1>S4U2>S4U3>S4U4>S4U5. The corresponding trends in the aqueous phase are S2U1>S2U3>S2U2>S2U5>S2U4 and S4U1>S4U2>S4U3>S4U5>S4U4. On the basis of the computed energy differences we can hypothesize that only the oxo‐thione forms of 2‐ and 4‐thiouracil should exist in the gas phase and in water solution. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 82: 44–52, 2001     

4‐(4‐Methoxy­phenyl­amino)‐3‐phenyl­azo‐3‐penten‐2‐one

The title compound, C₁₈H₁₉N₃O₂, was obtained by an azo‐coupling reaction with en­amino­nes and is composed of a planar azoen­amine skeleton which forms a six‐membered ring through a symmetrical intramolecular hydrogen bond. The compound was found to exist as an equilibrium mixture of major hydrazoimino and minor azoen­amine tautomers. Quantification of the relative contribution of the tautomeric forms is obscured by the existence of the hydrogen bond. Comparison of the results with those obtained for a similar structure revealed a substantial effect on the tautomeric equilibria of the nature of the substituent bonded to the amine nitro­gen.     

Prototropic tautomerism and microsolvation in antitumor drug imexon: a DFT study

Density functional theory method, at the B3LYP/6–311+G(d, p) level has been used to explore the geometries, relative energies, and electronic properties of all hypothetically possible prototropic tautomers of imexon. The specific interactions of the tautomeric forms of imexon with one and two solvating water molecules have been investigated. The relative stability order of the complexes remains unchanged upon interaction with one water molecule. The addition of a second water molecule, however, stabilizes the oxo-amino form more than the oxo-imino structure. The bulk water environment has been simulated by a combination of microhydration and the conductor-like polarizable continuum model. The energy profile corresponding to the prototopic tautomerisms connecting oxo-imino form with oxo-amino, hydroxyl-amino, and one rare tautomer has been studied. We found that the tautomerism activation barriers are high enough as to conclude that only the oxo-imino tautomer should be found in the gas phase. Our results present clear evidence that microhydration with one and two solvating water molecules considerably lower these barriers by a concerted multiple proton transfer mechanism.

     

The structure of the anti‐aging agent J147 used for treating Alzheimer's disease

The molecular structure of the anti‐aging agent J147 [systematic name: (E)‐N‐(2,4‐dimethylphenyl)‐2,2,2‐trifluoro‐N′‐(3‐methoxybenzylidene)acetohydrazide], C₁₈H₁₇F₃N₂O₂, has been determined at 150 K. The crystal structure corresponds to the minimum‐energy conformation in the gas phase calculated by density functional theory (DFT). 15 other conformations have been calculated and compared with the minimum, denoted 1111 . NMR spectroscopic data have been obtained and compared with those from Gauge Independent Atomic Orbital (GIAO) calculations. DFT calculations allow the reduction of the 16 possible rotamers to the four most stable (i.e. 1111 , 1112 , 1121 and 1222 ); in addition, the calculated barriers connecting these minima are low enough to permit their interconversion. Comparison of the NMR spectroscopic results, both experimental and calculated, point to the 1121 isomer being present in chloroform solution.     

Theoretical study addressing the effects of tautomerism and explicit/implicit water molecules on NQR and NMR parameters of tetrazole‐5‐thione

DFT/B3LYP calculations were employed to study the effects of tautomerism and explicit/implicit water molecules on Nuclear Quadrupole Resonance (NQR) and Nuclear Magnetic Resonance (NMR) tensors of nitrogen nuclei in tetrazole‐5‐thione structure. The obtained results revealed that nuclear quadrupole coupling constant (χ) and isotropic chemical shielding (σ_iso) values of nitrogen nuclei in tetrazole ring of five possible tautomeric forms of tetrazole‐5‐thione, i.e. two thione forms called tautomers A and E and three thiol forms called tautomers B, C, and D, were functions of resonance energy(E₂) values of nitrogen lone pairs. Furthermore, it was observed that by increasing participation of lone pairs of nitrogen atoms in the ring resonance interactions, the σ_iso values around them were increased, while their χ and q_zz values were decreased. However, the results indicated that with exception of tautomer B, the order of q_zz and χ values of nitrogen nuclei in tetrazole ring was exactly opposite of the order of resonance energy values for the same nitrogen nuclei in all tautomers and their mono‐hydrated complexes. In addition, a significant decrease was noticed in χ and q_zz values when a water molecule was put in different positions near the tetrazole ring in tautomers A–E. The mentioned result can be attributed to hydrogen bond formation between nitrogen nuclei and the oxygen of water. In mono‐hydrated complexes, the σ_iso values around nitrogen atoms acting as hydrogen donors in hydrogen bond formation (N―H….OH₂) were decreased, while its values were increased for nitrogen atoms acting as hydrogen acceptors in hydrogen bond formation(N….H―OH). Copyright © 2016 John Wiley & Sons, Ltd.