Substituent effects on the stability of 1,4‐benzodiazepin‐2‐one tautomers: A density functional study

The relative stability of 1,4‐benzodiazepin‐2‐one tautomers in the gas phase and model solvents was calculated at the M06 and ωB97XD levels of theory. The two density functionals were benchmarked earlier and demonstrated as excellent models to study tautomerism in a vast array of chemical systems. A number of commercially available 1,4‐benzodiazepin‐2‐ones were investigated computationally for the first time. In addition, some biologically active and newly devised benzodiazepines were considered, which may be important in designing structures with desired (bio)chemical features. Special attention was paid to determine substituent effects on the Gibbs free energies of keto, enol, and iminol forms for each respective benzodiazepine. It was demonstrated that (i) the replacement of the benzene ring by the heterocyclic ring in the benzodiazepine system may stabilize the iminol tautomer, and (ii) the electron‐withdrawing substituent at the C3‐position of the respective benzodiazepine may stabilize the enol tautomer relative to the parent keto form. It is concluded that substituent effects may govern the chemical reactivity and biological properties of selected benzodiazepines.     

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     

Voltammetric Determination of Trace Amounts of 2‐Methyl‐4,6‐Dinitrophenol at a Silver Solid Amalgam Electrode

The voltammetric behavior of 2‐methyl‐4,6‐dinitrophenol was investigated by differential pulse voltammetry (DPV) at a nontoxic mercury meniscus‐modified silver solid amalgam electrode (m‐AgSAE). Conditions have been found for its determination by DPV at m‐AgSAE in the concentration range of 0.2 to 1 μmol L^?1.     

2-酰基-1,3-环己二酮异构化反应中1,3-H和1,5-H迁移的理论研究

基于2-酰基1,3-环己二酮异构化反应,本文用密度泛函理论对文献报道的和我们设计的机理进行了系统研究。对反应中可能的速控步骤1,3-H和1,5-H迁移的过渡态结构和能垒进行了优化和计算。结果表明：本文设计的包括两个连续的1,5-酰基迁移和1,5-H迁移的反应机理,在动力学上更占优势。为了考察溶剂环境对反应的影响,本文分别研究了溶剂三乙胺和水对速度控制步骤1,3-H和1,5-H迁移的催化效应,揭示了两种催化剂对1,3-H和1,5-H迁移催化作用的差异。     

New insight into the photochromic mechanism of 1,3‐diphenyl‐4‐(4‐fluoro)benzal‐5‐pyrazolone N(4)‐phenyl semicarbazone

Density functional theory (DFT) calculation has been carried out to investigate the photochromic mechanism of 1, 3‐diphenyl‐4‐(4‐fluoro)benzal‐5‐pyrazolone N(4)‐phenyl semicarbazone. The novel mechanism, proposed by us, has different reaction pathway between the forward and the reverse process. The energy barrier of the forward direction was calculated to be significantly larger than that of the reverse direction (30.35 kcal/mol to 9.88 kcal/mol), which confirms the experimental observation that the forward process needs irradiation of light while the reverse one will take place easily when heated. The solvent effect on the relative stabilities of those isomers that may involve in the reaction has also been investigated by applying the polarizable continuum model (PCM) of the self‐consistent reaction field theory. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Density functional theory study of tautomerization of 2‐aminothiazole in the gas phase and in solution

The amino/imino tautomeric equilibrium in the isolated, mono‐, di‐, and trihydrate forms and dimer of 2‐aminothiazole, and the effects of hydration or self‐assistance on the transition state structures corresponding to proton transfer from the amino to imino form, have been investigated by the B3LYP method in conjunction with 6‐31+G(d,p) and 6‐311+G(3df,2p) basis sets in the gas phase and in solution. The amino form has been found to be the predominant tautomer. The tautomeric barrier heights for water‐ and self‐assisted tautomerization reactions are significantly lower than that from the amino to imino form by the intramolecular proton transfer, showing the catalytic effect of water molecule(s) and the important role of 2‐aminothiazole itself for intermolecular proton transfer. Comparison between the tautomeric barriers demonstrates that the self‐association tautomerization through the dimerization is the most favorable pathway. Bulk solvent effects have been taken into account using the polarizable continuum model (PCM) of water and CCl₄. The polar medium is favorable for the population of the imino form. The amino/imino equilibrium is also analyzed using the aromaticity index nucleus‐independent chemical shift (NICS); the NICS values for the amino form (about ?10 ppm) are more negative than the imino species (about ?8 ppm), showing that the amino form is more stable. The time‐dependent density functional theory (TDDFT) calculations of electronic absorption spectra suggest that the λ_max of dimer is 255 nm. The oscillator strength of the imino forms is less than the amino form, and increases with the polarity of the solvents. All calculations for the tautomerization of 2‐aminothiazole are in reasonable line with the available experiments. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

A DFT study of solvation effects on the tautomeric equilibrium and catalytic ylide generation of thiamin models

Thiamin diphosphate (ThDP) is the biologically active form of vitamin B1 and an essential cofactor for a number of enzymes. The effect of solvent polarity on the tautomeric equilibria of ThDP using three model systems of the 4'-aminopyrimidine ring is studied by density functional theory calculations (B3LYP/6-311+G(d,p)//B3LYP/6-31G(d)) in the gas phase and selected solvents (cyclohexane, ether, dichloroethane, and water). Solvation effects are investigated using three different schemes: implicit solvation by a continuum model, explicit solvation by inclusion of three water molecules mimicking the first solvation shell of the enzymatic environment, and by a mixed implicit/explicit solvation model. The 4'-aminopyrimidine tautomer is more stable than the 1',4'-iminopyrimidine tautomer in all solvation schemes employed; however, the trend for the stabilities of the 1',4'-iminopyrimidine tautomer in the solvents depends on the specific ThDP-model. Formation of the catalytic important ylide for ThDP-dependent enzymes by deprotonation of ThDP(C2) is also investigated by localization of transition states for two possible pathways. Only the less stable tautomer, 1',4'-iminopyrimidine ThDP, is able to form the catalytic active ylide. Generation of the ylide through a direct intramolecular proton transfer from ThDP(C2) to the ThDP(N4') nitrogen lone pair is favored by 6 kcal/mol in the gas phase, as compared to a water-mediated ylide generation. However, inclusion of a dielectric medium reduces this difference dramatically. Furthermore, inclusion of two water molecules to model the apoenzymatic environment lowers the activation energies of both direct and water-mediated ylide generation.     

Synthesis of 4,6‐Dimethyldibenzothiophene and 1,2,3,4‐Tetrahydro‐4,6‐dimethyldibenzothiophene via Tilak Annulation

1,2,3,4‐Tetrahydro‐4,6‐dimethyldibenzothiophene was prepared by coupling 2‐bromo‐3‐methylcyclohexanone with 2‐methylbenzenethiol and annulating the product with the aid of polyphosphoric acid. A mixture of 1,2,3,4‐tetrahydro‐4,6‐dimethyldibenzothiophene and 4,6‐dimethyldibenzothiophene was prepared by coupling 2‐bromo‐3‐methylcyclohex‐2‐en‐1‐one with 2‐methylbenzenethiol and annulating the product with the aid of polyphosphoric acid. 2‐Bromo‐3‐methylcyclohexanone was synthesized by conjugate addition of Me₃Al to 2‐bromocyclohex‐2‐en‐1‐one with CuBr as catalyst and 2‐bromo‐3‐methylcyclohex‐2‐en‐1‐one by bromination? elimination of 3‐methylcyclohex‐2‐en‐1‐one. 1,2,3,4,4a,9b‐Hexahydro‐4,6‐dimethyldibenzothiophene was prepared by reduction of 1,2,3,4‐tetrahydro‐4,6‐dimethyldibenzothiophene with Zn and CF₃COOH.     

Isotopic splitting patterns in the 13C NMR spectra of some partially deuterated 1‐aryl‐2‐(phenyldiazenyl)butane‐1,3‐dione and 4‐hydroxy‐3‐(phenyldiazenyl)‐2H‐chromen‐2‐one: evidence for elucidation of tautomeric forms

Nuclear magnetic resonance spectra of synthesized azo dyes derived from aniline derivatives in reaction with benzoylacetone and 4‐hydroxycoumarin were studied in both CDCl₃ and (CD₃)₂SO (two drops of D₂O were added into solutions of dyes). All dyes showed intramolecular hydrogen bonding. Dyes derived from o‐nitro aniline in the reaction with benzoylacetone, and 4‐hydroxycoumarin showed bifurcated intramolecular hydrogen bonds. The solvent‐substrate proton exchange of dyes derived from benzoylacetone and 4‐hydroxycoumarin was examined in the presence of two drops of D₂O. Among ten dye samples, two dyes derived from benzoylacetone did not show deuteration, three dyes showed partial deuteration and five dyes showed full deuteration under similar conditions. For the partially deuterated dyes the β‐isotope effect in ¹³C splitting was investigated and was used for the determination of the predominant tautomeric form. Copyright © 2016 John Wiley & Sons, Ltd.     

Isotopic effect on tautomeric behavior of 5‐(2,6‐disubstituted‐aryloxy)‐tetrazoles

Isotopic effect on tautomeric behaviors of the synthesized 5‐phenoxy‐ (1a), 5‐(2,6‐dimethylphenoxy)‐ (1b), 5‐(2,6‐diisopropylphenoxy)‐ (1c), 5‐(2,6‐dimethoxyphenoxy)‐ (1d) and 5‐(4‐methylphenoxy)‐tetrazole (1e) were investigated in DMSO‐d₆ by adding one drop of D₂O. Among 1a–e, 1a, 1d and 1e show small rotational barrier around C5? O1 and O1? C6 while in 1b and 1c there are distinguishable rotational barrier about that bonds. The ¹H NMR spectra of 1b and 1c show slightly different chemical shifts for two methyl and isopropyl groups on those phenyl ring, respectively, while the chemical shifts difference (Δδ) between two methyl and two isopropyl groups were enhanced by adding D₂O. The ¹³C NMR spectra of 1b show two overlapped singlets for methyl groups after adding D₂O. Representatively, the calculations of compound 1c were performed with GAUSSIAN‐03and the rotational barrier about C5? O1 and between isopropyl group and phenyl ring in 1c was calculated with B3LYP/6‐31G(d) basis set. Copyright © 2011 John Wiley & Sons, Ltd.     

Quantum chemistry aspects of the solvent effects on the ene reaction of 1‐Phenyl‐1,3,4‐triazolin‐2,5‐dione and 2‐methyl‐2‐butene

A density functional theory study was used to investigate the quantum aspects of the solvent effects on the kinetic and mechanism of the ene reaction of 1‐phenyl‐1,3,4‐triazolin‐2,5‐dione and 2‐methyl‐2‐butene. Using the B3LYP/6–311++ G(d,p) level of the theory, reaction rates have been calculated in the various solvents and good agreement with the experimental data has been obtained. Natural bond orbital analysis has been applied to calculate the stabilization energy of N18? H19 bond during the reaction. Topological analysis of quantum theory of atom in molecule (QTAIM) studies for the electron charge density in the bond critical point (BCP) of N18? H19 bond of the transition states (TSs) in different solvents shows a linear correlation with the interaction energy. It is also seen form the QTAIM analysis that increase in the electron density in the BCP of N18? H19, raises the corresponding vibrational frequency. Average calculated ratio of 0.37 for kinetic energy density to local potential energy density at the BCPs as functions of N18? H19 bond length in different media confirmed covalent nature of this bond. Using the concepts of the global electrophilicity index, chemical hardness and electronic chemical potentials, some correlations with the rate constants and interaction energy have been established. Mechanism and kinetic studies on 1‐phenyl‐1,3,4‐triazolin‐2,5‐dione and 2‐methyl‐2‐butene ene reaction suggests that the reaction rate will boost with interaction energy enhancement. Interaction energy of the TS depends on the solvent nature and is directly related to electron density of the bonds involved in the reaction proceeding, global electrophilicity index and electronic chemical potential. However, the chemical hardness relationship is reversed. Finally, an interesting and direct correlation between the imaginary vibrational frequency of the N18? H19 critical bond and its electron density at the TS has been obtained. © 2014 Wiley Periodicals, Inc.     

N-甲基b-磺内酰胺氨解反应机理的理论研究

The aminolysis and the effect of water on the aminolysis processes of n-methyl β-sultam have been studied using density functional theory （DFF） method at the B3LYP/6-31G＊ level. The stationary structures and energies have been investigated for both reactions to find two different reaction channels. Specific and general solvent effects have been evaluated and the most favored pathway was found. The presence of solvent disfavors the reaction, whereas the participation of water in the aminolysis reaction plays a positive role and reduces the activation energy greatly. All transition states in the assisted aminolysis are 35-70 kJ/mol lower than those for the non-assisted reaction.     

Theoretical Study on Gas—phase Pyrolytic Reactions of N—Ethyl,Isopropyl and N—t—Butyl Substituted 2—Aminopyrazine

Density functional theory (DFT) and ab initio methods were used to study gas‐phase pyrolytic reaction mechanisms of iV‐ethyl, N‐isopropyl and N‐t‐butyl substituted 2‐aminopyrazine at B3LYP/6–31G* and MP2/6–31G*, respectively. Single‐point energies of all optimized molecular geometries were calculated at B3LYP/6–311 + G(2d,p) level. Results show that the pyrolytic reactions were carried out through a unimolecular first‐order mechanism which were caused by the migration of atom H(17) via a six‐member ring transition state. The activation energies which were verified by vibrational analysis and correlated with zero‐point energies along the reaction channel at B3LYP/6–311 + G(2d,p) level were 252.02 kJ. mo^?1 (N‐ethyl substituted), 235.92 kJ‐mol^?1 (N‐t‐isopropyl substituted) and 234.27 kJ‐mol^?1 (N‐t‐butyl substituted), respectively. The results were in good agreement with available experimental data.     

Experimental and Theoretical Studies on the Rearrangement of 2‐Oxoazepane α,α‐Amino Acids into 2′‐Oxopiperidine β2,3,3‐Amino Acids: An Example of Intramolecular Catalysis

Enantiopure β‐amino acids represent interesting scaffolds for peptidomimetics, foldamers and bioactive compounds. However, the synthesis of highly substituted analogues is still a major challenge. Herein, we describe the spontaneous rearrangement of 4‐carboxy‐2‐oxoazepane α,α‐amino acids to lead to 2′‐oxopiperidine‐containing β^2,3,3‐amino acids, upon basic or acid hydrolysis of the 2‐oxoazepane α,α‐amino acid ester. Under acidic conditions, a totally stereoselective synthetic route has been developed. The reordering process involved the spontaneous breakdown of an amide bond, which typically requires strong conditions, and the formation of a new bond leading to the six‐membered heterocycle. A quantum mechanical study was carried out to obtain insight into the remarkable ease of this rearrangement, which occurs at room temperature, either in solution or upon storage of the 4‐carboxylic acid substituted 2‐oxoazepane derivatives. This theoretical study suggests that the rearrangement process occurs through a concerted mechanism, in which the energy of the transition states can be lowered by the participation of a catalytic water molecule. Interestingly, it also suggested a role for the carboxylic acid at position 4 of the 2‐oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis.     

Ab initio study on tautomerism of 2-thiouracil in the gas phase and in solution

Ab initio geometry optimizations were carried out at the HF/3-21G and HF/6-31+G^** levels for the six tautomeric forms of 2-thiouracil (2TU, 2TU1, 2TU2, 2TU3, 2TU4, 2TU5) in the gas phase and in solution. To obtain a more definitive estimate of the relative stabilities for 2-thiouracil tautomers in the gas phase, single-point MP2/6-31+G^** calculations were performed on the HF/6-31+G^** optimized geometries. The tautomeric equilibria in 1,4-dioxane (=2.21), acetonitrile (=38), and in water (=78.54) were studied using the self-consistent reaction field (SCRF) theory. The calculated relative free energies indicated that 2TU is the energetically preferred tautomer in the gas phase and in solution. The stability order of 2-thiouracil tautomers depends on the level of theory and the dielectric constant of the solvent. The obtained results are compared with the available experimental data.     

Preparation of Partially Hydrogenated 4,6‐Dimethyldibenzothiophenes

The synthesis of three key intermediates of the hydrogenation pathway in the hydrodesulfurization of 4,6‐dimethyldibenzothiophene (4,6‐DM‐DBT; 1 ) is described. The hydrogenated derivatives 1,2,3,4‐tetrahydro‐4,6‐dimethyldibenzothiophene (= 4,6‐dimethyl‐1,2,3,4‐tetrahydrodibenzothiophene; 4,6‐DM‐TH‐DBT; 2 ), 1,2,3,4,4a,9b‐hexahydro‐4,6‐dimethyldibenzothiophene (= 4,6‐dimethyl‐1,2,3,4,4a,9b‐hexahydrodibenzothiophene; 4,6‐DM‐HH‐DBT; 3 ), and dodecahydro‐4,6‐dimethyldibenzothiophene (= 4,6‐dimethylperhydrodibenzothiophene; 4,6‐DM‐PH‐DBT; 4 ) were prepared by direct hydrogenation of 1 . The reactions were carried out in continuous and batch reactors by using metal sulfide as well as noble‐metal catalysts. The influence of the reaction conditions on the formation of the products and the distribution of their stereoisomers was studied in detail. The isomers of the main products were isolated and characterized by NMR, GC/MS/MS, and X‐ray crystal‐structure diffractometry.     

Theoretical investigation on the dissociation of (R)‐benzoin catalyzed by benzaldehyde lyase

Benzaldehyde lyase (BAL) is a versatile thiamin diphosphate (THDP)‐dependent enzyme with widespread synthetic applications in industry. Besides lyase activity, BAL also performs the functions as carboligase and decarboxylase. Unlike many other THDP‐dependent enzymes, the active center of BAL is devoid of any acid‐base amino acid residues except Glu50 and His29, and therefore, the catalytic mechanism of BAL is unusual. In this article, the dissociation mechanism of (R)‐benzoin to benzaldehyde catalyzed by BAL has been studied by using density functional theory method. The calculation results indicate that the whole reaction consists of four elementary steps, and at least two steps contribute to rate‐limiting. A big difference with other THDP‐dependent enzymes is that, in the first stage of the reaction, the ligation of substrate and THDP ylide is not companied by proton transfer, and in the subsequent transition states and intermediates, the carbonyl oxygen always exists in the form of anion. Gln113, His29, and 4′‐amino group of THDP are found to have the function to stabilize the transition states and intermediates. His29 acts as the proton acceptor in step 2 and proton donor in step 3 using one water molecule as mediator. © 2013 Wiley Periodicals, Inc.     

Fe3O4@TiO2@O2PO2(CH2)NHSO3H as a novel nanomagnetic catalyst: Application to the preparation of 2‐amino‐4,6‐diphenylnicotinonitriles via anomeric‐based oxidation

A new, green and reusable nanomagnetic heterogeneous catalyst, namely Fe₃O₄@TiO₂@O₂PO₂(CH₂)NHSO₃H, was synthesized and fully characterized using suitable techniques such as infrared spectroscopy, X‐ray diffraction, scanning and transmission electron microscopies, thermogravimetry, vibrating sample magnetometry and energy‐dispersive X‐ray spectroscopy. The applicability of the constructed heterogeneous core–shell catalyst as a promoter was successfully explored for the synthesis of 2‐amino‐4,6‐diphenylnicotinonitrile derivatives upon the reaction of a good range of aromatic aldehydes, acetophenone derivatives, malononitrile and ammonium acetate. The desired products were obtained with good to high yields in short reaction times under solvent‐free conditions. The suggested mechanism offers an anomeric‐based oxidation route to the products in the final step of the synthetic pathway.     

Experimental and Theoretical Investigation of One‐pot Synthesis of 2‐Amino‐4H‐chromenes Catalyzed by Basic‐functionalized Ionic Liquids

An efficient and environmentally benign procedure for the reactions of three components condensation of salicylaldehyde and two different CH acids to give 2‐amino‐4H‐chromenes catalyzed by a series of basic‐functionalized ionic liquids was reported. The most possible reaction pathway was proposed for the first time by performing density functional theory (DFT) calculations. Both cation and anion of [Bmim]OH have a cooperative effect on the reaction. [Bmim]⁺ increases the electrophilicity of salicylaldehyde via intermolecular hydrogen bonds, while OH^? deprives proton of two CH acids to strengthen their nucleophilic ability.     

Mechanistic study on gold(I)‐catalyzed crosscoupling of diazo compounds: A DFT study

The reaction mechanisms of the gold(I)‐catalyzed cross‐coupling reaction of aryldiazoacetate R1 with vinyldiazoacetate R2 leading to N‐substituted pyrazoles have been theoretically investigated using density functional theory calculations. Two possible reaction mechanisms were examined and discussed. The preferred reaction mechanism (mechanism A) can be characterized by five steps: the formation of the gold carbenoid A2 via the attack of catalyst to R1 (step I), nucleophilic addition of another reactant R2 to generate intermediate A3 (step II), intramolecular cyclization of A3 to form intermediate A4 (step III), hydrogen migration to give intermediate A5 (step IV), and catalyst elimination affording the final product P1 (step V). Step IV is found to be the rate‐determining step with an overall free energy barrier of 28.3 kcal/mol. Our calculated results are in good agreement with the experimental observations. The present study may provide a useful guide for understanding these kinds of gold(I)‐catalyzed cross‐coupling reactions of diazo compounds.