Tautomerism of the antiepileptic drug Felbamate: A DFT study

The Felbamate is a novel anticonvulsant and neuropathic pain drug that can exist as three possible tautomers. Herein, employing density functional theory (DFT) and handling the solvent effects with the PCM model, the structural parameters, energy behavior, natural bond orbital analysis (NBO), as well as the tautomerism of Felbamate are investigated. F1 is the kinetically and thermodynamically most stable tautomer of Felbamate, which contains the amide group in each of the carbamate moieties. The calculated NMR chemical shifts and IR vibrational frequencies are in good agreement with the experimental values, confirming the suitability of the optimized geometry for Felbamate. The tautomerization reaction of F1 to each of the other tautomers occurs via an intramolecular proton transfer. This reaction affects considerably the structural parameters and atomic charges of the Felbamate molecule. A large HOMO-LUMO energy gap implies a high stability of the F1 tautomer.     

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.     

A first-principle DFT study of solvent effects on metiamide tautomers and imaginary interactions with H<Subscript>2</Subscript>-receptors

Metiamide is a class of medications called H₂-receptor antagonist or H₂ blockers. It decreases the amount of acid made in the stomach. It is commonly used in the treatment for peptic ulcer disease and gastroesophageal reflux disease. In this study, the metiamide tautomer stability, structural data, HOMO and LUMO (energies and shapes), ΔΕ _HOMO–LUMO gaps, UV–visible data and graphs, dipole moments, Mulliken charges, and thermodynamic and kinetic stabilities in aqueous media as a biological solvent and some of the different media (vacuum, H₂O, Et-OH and DMSO) were investigated for the tautomers of metiamide by the density functional theory DFT-B3LYP/6-31G* method. The results presented that the probability of the adaptability and compatibility of which tautomer (T1–T6) are better than the other tautomers for interactions with the pattern and structural map of the H₂-receptor. The diversities of the interaction points and mosaic patterns of the T3 and T4 tautomers in H₂O media with the imaginary H₂-receptor were investigated.     

Exploring the impacts of the vinylogous anomeric effect on the synchronous early and late transition states of the hydrogen molecule elimination reactions of cis-3,6-dihalocyclohexa-1,4-dienes

LC-ωPBE, B3LYP, and M06-2X methods with the 6–311+G** basis set on all atoms and natural bond orbital (NBO) interpretation were performed to investigate the roles and contributions of the effective factors on the potential energy surfaces of the hydrogen molecule elimination reactions of cyclohexa-1,4-diene (1) and its cis-3,6-dihalo derivatives [halogen=F (2), Cl (3), Br (4)] to hydrogen molecule and their corresponding aromatic rings. The ring puckering in compound 2 (which results from the repulsive electrostatic interactions between the natural bond orbital dipole moments of two C-F bonds) shortens the allylic hydrogen atoms’ distance, leading to the smaller barrier height in compound 2 compared to that in compound 1. The barrier heights of the hydrogen molecule elimination reactions increase from compounds 2 to 4 while their corresponding exothermic characters decrease. The variations of the advancements of transition state structures (δB _av) reveal that the hydrogen molecule elimination reactions of compounds 2–4 do not obey the Hammond-Leffler postulate. In compound 2, the ring puckering shortens the allylic hydrogen distance (d _H8-H10) while d _H8-H10 values increase going from compounds 2 to 4, leading to the increase of their corresponding hydrogen molecule elimination reactions barrier heights. Interestingly, the variations of the vinylogous hyperconjugative anomeric effects justify the directions of the rings puckering going from compounds 2 to 4. The increase of the activation exchange components [PETR _(TS)-PETR _(GS)] going from compounds 2 to 4 correlates well with their corresponding hydrogen molecule elimination process barrier heights.     

Theoretical studies on tautomerism of imidazole-2-selenone

The tautomerism of all possible forms of imidazole selenone (ISe1–ISe6), induced by proton transfer was studied theoretically in different environments including gas phase, continuum solvent, and microhydrated environment with one explicit water molecule. The calculations were performed at the MP2 and CAM-B3LYP levels of theory, separately. It was found that the imidazole selenone, in the form of ISe3, is the most stable isomer in both gas phase and solvent. The activation energy for conversion of ISe3 to imidazole selenol (ISe6), as the second stable form, is 41.72 and 43.0 kcal/mol in the gas phase and water, respectively. The infrared spectral frequencies as well as the vibrational frequency shifts were reported and assigned to their corresponding vibrational modes. In addition, the variation of dipole moments and charges on the atoms with change of solvent was studied. The energies of HOMO, LUMO, and HOMO–LUMO gap were calculated in both gas phase and solvent. Specific solvent effects with addition of water molecule near the electrophilic centers of tautomers and the transition states of proton transfer, assisted by water molecule, were investigated. It was found that the water molecule can form different hydrogen bonds with the molecule. Aggregation of the isomers with water molecule does not change the order of stability of isomers, but proton transfer reaction assisted by a water molecule needs less energy than when the proton shifts through the intramolecular process.     

Influence of the methylene group between azadithiolate nitrogen atom and phenyl moiety on the protophilic properties of [FeFe]-hydrogenase model complexes

An [FeFe]-hydrogenase mimic 4 with functional benzyl moiety covalently linked to the azadithiolate ligand was synthesized. The structure, protonation, and electrochemical properties of 4 and a phenyl substituted analogue (coded as 3) were simultaneously studied to explore the influence of the methylene group between the bridgehead nitrogen atom and functional phenyl moiety on the protophilic properties of the model complexes. X-ray single crystal diffraction analysis revealed that the nitrogen atoms of 3 and 4 possessed sp ² and sp ³-hybridization, respectively. Although the light-driven electron transfer was prevented in the molecule of 4, the sp ³-hybridized nitrogen atom of 4 could be protonated in the presence of the proton acid to give the [4(NH)]⁺ cation. The generated positive charge could be reduced at ca. ?1.2 V versus Fc/Fc⁺ with a distinctly electrocatalytic proton reduction activity, whereas the proton reduction catalysed by 3 occurred at ca. ?1.45 V. The catalytic proton reductions of 3 and 4 followed ECCE and CECE mechanisms, respectively. It was noteworthy that the potential of 4 was remarkably anodic shifted and closer to that of the proton reduction catalysed by natural enzymes.     

DFT and MP2 Calculations on Tautomers and Water-Assisted Proton Transfer on 1,2,5-Oxadiazol-4,3-diamine

In this work a detailed quantum-chemical comparison of the relative stability of six tautomers of 1,2,5-oxadiazol-4,3-diamine studied in the gas phase and solution. Theoretical calculations are carried out by the density functional theory (DFT/B3LYP) and MP2 methods using the standard 311++G(d,p) basis set. The results indicate that A is the most stable form in the gas phase and also is the predominant tautomer in solution at the DFT and MP2 methods. The transition states of proton transfer reaction are calculated. The variation of dipole moments and charges on atoms are studied in various solvent. Specific solvent effects with addition of one water molecule near the electrophilic centers of tautomer investigated. Also the transition state of proton transfer assisted by a water molecule was investigated.     

A DFT/TDDFT Study on Excited State Process of a Novel Probe 4′-Fluoroflavonol

A novel fluorescent probe 4′-fluoroflavonol (4F) was reported by Serdiuk et al. (RSC Adv 6:42532, 2016) in a previous paper. Spectroscopic studies on excited-state proton transfer (ESPT) of 4F was mentioned, while the mechanism of ESPT for 4F isdeficiency. In this present work, based on the time dependent density functional theory (TDDFT), we investigated the excited-state intramolecular proton transfer (ESIPT) mechanism of 4F theoretically. The primary bond lengths, bond angles and the infrared (IR) vibrational spectra involved in the formation of hydrogen bonds vertified the intramolecular hydrogen bond was strengthened, which manifests the tendency of excited state proton transfer. According to the results of calculated potential energy curves along O–H coordinate, an about 13.18 kcal/mol barrier has been found in the S₀ state. However, a barrier of 3.29 kcal/mol was found in the S₁ state, which demonstrates that the proton transfer process is more likely to occur in the excited state. In other words, the proton transfer was facilitated by photoexcitation. Particularly, the study about ESIPT mechanism of 4F should be helpful for further understanding property of fisetin.     

Single crystal x-ray diffraction study of dioxane,pyrazine, and pyridine complexes of 3-(1-amino-2,2,2-trifluoroethylidene)-2-imino-1,1,4,5,6,7-hexafluoroindan

Single crystals of complexes of 3-(1-amino-2,2,2-trifluoroethylidene)-2-imino-1,1,4,5,6,7-hexafluoroindan (1) with 1,4-dioxane, pyrazine, and pyridine have been synthesized. Their structure was investigated by X-ray analysis. In crystals of the dioxane complex, compound 1 is present together with its tautomer — 2-amino-3-(1-imino-2,2,2-trifluoroethyl)-1,1,4,5,6,7-hexafluoroindene (1a), and these compounds are in an equilibrium ratio of ～60:40. Gas-phase quantum chemical calculations have been performed to examine the possibility of a tautomeric equilibrium of enaminoimine 1 in the corresponding complexes.     

Quantum chemical studies of azoles

The results of theoretical search for model transition states of the electrophilic substitution reaction in 2H-tetrazole (1) without the preliminary formation of N-protonated azolium salts are presented for two routes that were previously suggested by the authors and thermodynamically investigated: A, the attack of molecule 1 by the nucleophile (HO^–(aq)) to form the anion to which the electrophile H₃O⁺(aq)) is added and B, the attack of molecule 1 by the same electrophile followed by the addition of the same nucleophile to the specifically solvated protonated species formed in the preceding reaction step. The calculations were performed using the DFT/B3LYP/6-31G(d) method and the scanning procedure of the potential energy surface (PES). Both steps of route A turned out to be nearly barrierless, while in route B only its first step is barrierless and the second one is conjugated with passing an activation barrier of ～45 kcal mol^–1 between non-interacting or weakly interacting reactants and electrophilic substitution products. Unlike the specifically solvated protonated species of 1H-tetrazole in an aqueous solution, a similar species of 2H-tetrazole does not form a prereaction complex with the attacking nucleophile (HO^–(aq)) and the five-membered ring is destroyed in fact in the nitrogen-containing reaction product formed after passing the activation barrier. The optimized structure of the transition state differs strongly from the nitrogen-containing structure of the reaction product with the destroyed ring, which was found by scanning of the PES.     

Photochemical reactions of di(naphthyl-1-methyl)mercury in various solvents

It was found that the photolysis of di(naphthyl-1-methyl)mercury (1) gives 1,2-dinaphthylethane (2) in heptane and benzene solvents and 2 and 1-methylnaphthalene in isopropanol and acetonitrile. Irradiation of 1 in carbon tetrachloride gives 2 and ClHgCH₂C₁₀H₇ as primary reaction products, while the chloride is further photolyzed to 2. Quantum yields of the photolysis of 1 are high and equal to unity almost for all solvents. The chloride photodecomposition yield is an order of magnitude lower (0.1).     

Recovery of host crystals from inclusion crystals of <Emphasis Type="Italic">p-tert-</Emphasis>butylcalix[4]arene and <Emphasis Type="Italic">p-tert</Emphasis>-butylthiacalix[4]arene by the treatment with a solvent and/or supercritical CO<Subscript>2</Subscript>

Upon stirring inclusion crystals of p-tert-butylthiacalix[4]arene (2) in solvents with heating, guest compounds were efficiently desorbed to yield guest-free crystals. More specifically, upon treatment with methanol, the exchange of guest compounds with methanol in the crystals, followed by the desorption of the methanol afforded metastable host crystals 2β, whereas, upon treatment with heptane, the dissolution of the inclusion crystals and simultaneous crystallization of compound 2 afforded stable host crystals 2α. Further, a host crystal of p-tert-butylcalix[4]arene (1) was recovered by the treatment of 2:1 (host/guest) inclusion crystals of compound 1 with supercritical carbon dioxide (scCO₂), and through the combination of the guest exchange of 1:1 inclusion crystals of compound 1 with hexane and scCO₂ treatment of the resulting 2:1 inclusion crystals 1₂·hexane. Although the recovered host crystal of compound 1 contained a small amount of CO₂, it could be reused for the inclusion of organic compounds.     

Gelation capability of cysteine-modified cyclo(L-Lys-L-Lys)s dominated by Fmoc and Trt protecting groups

A series of symmetrical peptidomimetics(3–8) based on cysteine-modified cyclo(L-Lys-L-Lys)s were synthesized, and their gelation capability in organic solvents was dominated by fluorenylmethyloxycarbonyl(Fmoc) and triphenylmethyl(Trt) protecting groups and the exchange of thiol-to-disulfide as well. The peptidomimetics holding Trt(3 and 4) showed no gel performance, while the Fmoc groups promoted 5 and 6 to give rise to thermo-reversible organogels in a number of organic solvents. The self-assembled fibrillar networks were distinctly evidenced in the organogels by transmission electron microscopy(TEM) and scanning electron microscopy(SEM) observations. Fourier transform infrared spectroscopy(FT-IR) and fluorescence analyses revealed that the hydrogen bonding and ?-? stacking play as major driving forces for the self-assembly of these organogelators. A ?-turn secondary structure was deduced for the organogel of 6 by virtue of X-ray diffraction, FT-IR and circular dichroism(CD) measurements, and an interdigitated bilayer structure was also presented.     

A DFT study on the geometry,spectroscopic properties,and tautomerization of the local anaesthetic drug prilocaine

The prilocaine is a significant amino amide local anaesthetic. This drug can exist as three possible tautomers. Herein, by using density functional theory (DFT), and handling the solvent effects with the PCM model, the structure, energetic behavior, kinetics and mechanism of tautomerization, as well as the natural bond orbital analysis (NBO) of the prilocaine are reported. P1 is the most stable tautomer of the prilocaine, which can be tautomerized to two other tautomers via the intramolecular-proton transfer. Good agreement between the calculated NMR chemical shifts and IR vibrational frequencies with the experimental values approves the suitability of the optimized geometry for the prilocaine. A large HOMO-LUMO energy gap implies a high stability of the prilocaine.     

Solvent,substituent, and dimerization effects on the ring-opening mechanisms of monosilacyclopropylidenoids: a theoretical study

Density functional theory and ab initio computations elucidated the ring-opening of substituted (R = –CF₃, –CN, –CH₃, –H, –NH₂, –OCH₃, –OH, –SiH₃) 1-bromo–1-lithiosilirane 1 and 2-bromo–2-lithiosilirane 2 to LiBr complexes of 2-silaallene and 1-silaallene, respectively. Formally, two competitive pathways can be considered. The ring-opening reaction can take place through a concerted manner via TS3. Alternatively, the reaction may proceed in a stepwise fashion with the intermediacy of a free silacyclopropylidene–LiBr complex 7. In both cases, the position of the substituents determines the kinetic of the reactions. The structures with an electron-donating group are generally unstable, whereas the silacyclopropylidenoids bearing electron-withdrawing substituents are particularly stable species. Here, we propose the ring-opening of 5a–h to corresponding LiBr complexes of 2-silaallenes can proceed in both concerted and stepwise mechanism except for –H, –CH₃, and –SiH₃. The obtained activation energies for the ring-openings of 5a–h to related 2-silaallenes are too high for a reaction at room temperature with up to 61.4 kcal/mol. In contrast, the activation energy barriers for the isomerization of 6a–h to the LiBr complexes of 1-silaallenes was determined to be relatively low at the B3LYP/6-31+G(d,p), M06/6-31+G(d,p), and MP2/6-31+G(d,p) levels. Moreover, we have also investigated the solvent effect on the unsubstituted models using both implicit and explicit solvation models. The energy barriers of the solvated models are found to be slightly higher than the results of gas phase calculations. Additionally, the ring-opening of dimer 6 (6–Dim) is also calculated for the ring-opening mechanism with the energy barrier of 3.7 kcal/mol at B3LYP/6-31+G(d,p) level of theory.     

Comparative studies of photophysical and electrochemical properties of sulfur-containing substituted metal-free and metallophthalocyanines

The synthesis, photophysical and electrochemical properties of soluble sulfur-containing 4-(methylthio) benzenethiol substituted, non-peripherally metal-free and metallo (Zn, Ga, Co, and Mn) phthalocyanine complexes (2–6) are reported for the first time. The new phthalocyanines have been characterized by FT-IR spectroscopy, ¹H-NMR, ¹³C-NMR, mass and UV–Vis spectroscopy techniques. Spectroscopic properties of these compounds were investigated in different solvents. Spectral and photophysical (fluorescence quantum yield) properties of metal free (2), zinc(II) (3), and gallium(III) phthalocyanines (4) were reported in different solvents toluene, tetrahydrofuran, and dimethyl sulfoxide. These results suggest that the solvents play role on the fluorescence quantum yields Φ _F of the synthesized complexes (2–4). The electrochemical studies exhibit that while complexes (3) and (4) give only Pc ring-based redox processes, complexes (5) and (6) give both metal and ring-based redox reactions due to the energy level of metal in the Pc core lie between the HOMO and the LUMO of the ring.     

Synthesis,characterization, and crystal structure of cobalt(II) and zinc(II) complexes with a bulky Schiff base derived from rimantadine

Two novel complexes, C₃₈H₄₈CoN₂O₂ (I) and C₃₈H₄₈N₂O₂Zn (II), were prepared through an analogous procedure with a corresponding metal chloride and a bulky Schiff base ligand (HL) which derived from rimantadine and salicylaldehyde in appropriate solvents, respectively. They were structurally characterized by the means of IR, UV-Vis, elemental analysis, molar conductance, PXRD and single-crystal X-ray diffraction (CIF files nos. 946735 (I), 893304 (II)). Single-crystal X-ray diffraction analysis reveals that I belongs to the triclinic system, \(P\overline 1 \) space group; each asymmetric unit consists of one cobalt(II) complex and one lattice ethanol molecule. In each complex molecule, cobalt(II) atom is four-coordinated via two oxygen atoms and two nitrogen atoms from the deprotonated Schiff base ligands, forming an approximate planar geometry. The crystal structure also involves strong O–H···O intermolecular hydrogen bonds between the solvent alcoholic and phenol O atoms of complex molecule. Complex II belongs to the monoclinic system, Cc space group. Each asymmetric unit consists of one zinc(II) ion and two deprotonated ligands. Zinc(II) atom lies on a twofold rotation axis and is four-coordinated via two nitrogen atoms and two oxygen atoms from the Schiff base ligands, forming a distorted tetrahedral geometry.     

Structure of methyl-7-methoxy-7-phenyl-6-<Emphasis Type="Italic">endo</Emphasis>-halobicyclo[3.1.1]heptane-6-<Emphasis Type="Italic">exo</Emphasis>-carboxylate diastereomers in single crystals

The structure of diastereomeric methyl-7-anti-methoxy-7-syn-phenyl-and methyl-7-syn-methoxy-7-anti-phenyl-6-endo-bromobicyclo[3.1.1]heptane-6-exo-carboxylates 2a and 3a and their chlorine-and iodine-substituted analogs 2b and 3c was studied by XRD. The diastereomers differ in the geometrical parameters of the carbon framework of the molecules. The C(1)-C(2)-C(3)-C(4)-C(5)-C(6) six-membered ring is in the intermediate conformation between envelope and chair in structures 2 and envelope in structures 3. In compound 2a, the cyclobutane fragment has a higher degree of folding than in 3a; one of the possible reasons for that is the donor-acceptor interaction between the 6-methoxycarboxylic and 7-methoxy groups in molecule 2a.     

Peculiarities of exited state intramolecular proton transfer in 2-amino-3-(2′-benzazolyl)-quinolines

It has been shown that a low fluorescence quantum yield of 2-amino-3-(2′-benzoxazolyl)-quinoline (ABO) and 2-amino-3-(2′-benzothiazolyl)-quinoline (ABT) is due to the relaxation process caused by excited state intramolecular proton transfer (ESIPT). Quantum-chemical calculations have revealed that ESIPT in these compounds is characterized by overcoming a potential barrier, with the lower basicity of the proton-accepting moiety in ABO resulting in a higher barrier than in ABT and, thereby, determining a substantial difference in their fluorescence quantum yields.