Thiol Tautomer Research Articles

Ergothioneine and related histidine derivatives in the gas phase: tautomer structures determined by IRMPD spectroscopy and theory.

l-Ergothioneine (ET) is a sulfur-containing derivative of the amino acid histidine that offers unique antioxidant properties. The enzyme independent redox-chemistry of ET relies on the availability of the thiol tautomer to allow oxidative formation of disulfide bridges, i.e., the tautomeric equilibrium. To study the intrinsic properties of ET the tautomeric equilibrium is studied in the gas-phase by infrared multiphoton dissociation (IRMPD) spectroscopy. The IR ion spectra of isolated molecular ions of ET and of the biosynthetic precursors of ET, i.e., hercynine and Nε-methyl-hercynine are acquired. The analyte structures are independently investigated by density functional theory (DFT) and computed linear IR-spectra of tautomer ion structures are compared with the gas-phase spectra for identification. For the molecular ion of ET the simulated IR spectra of thione and thiol structures match the recorded IRMPD spectrum and that prevents an individual structure assignment. On the other hand, theory suggests that ET adopts a thione tautomer in MeOH solution which could be carried over from the condensed phase to gas phase and could be kinetically trapped after effective electrospray phase transfer and desolvation. Such a non-thermal behavior is also found for the molecular ions of protonated hercynine and Nε-methyl-hercynine. Contrary to that, the sodium complex ions of ET, hercynine and Nε-methyl-hercynine adopt the respective ground structures predicted by theory, which are reliably identified spectroscopically. For ET the thione tautomer is by far the most stable isomer in the sodium complex molecular ion.

A DFT Study of Some Structural and Spectral Properties of 4-Methoxyacetophenone Thiosemicarbazone and Its Complexes with Some Transition Metal Chlorides: Potent Antimicrobial Agents

Recent studies have shown that 4-methoxyacetophenone thiosemicarbazone (MAPTSC) and its complexes with some transition metal chlorides are potent antimicrobial agents. To deepen the understanding of their structure-activity relationships necessary for rational drug design, their structural and spectral properties, along with thione-thiol tautomerism of MAPTSC, have been studied herein using the density functional theory (DFT). From our results, the thione tautomer of MAPTSC is more stable than the thiol counterpart in ethanolic solution, and thione-to-thiol tautomerization is highly precluded at ambient temperature (25°C) by a high barrier height ≈46.41 kcal/mol. MAPTSC can therefore exist as a mixture of the thione (major) and thiol (minor) tautomers in ethanolic solution at room and higher temperatures. Conformational analysis has revealed five possible conformers of the thione tautomer, of which two are stable enough to be isolated at 25°C. Based on our computed values of MAPTSC-metal(II) binding energies, enthalpies, and Gibbs free energies, the thione tautomer of MAPTSC exhibits a higher affinity for the d8 metal ions Ni(II), Pd(II), and Pt(II) and can therefore efficiently chelate them in chemical and biological systems. Natural population analysis has revealed ligand-metal charge transfer in the MAPTSC complexes studied. A good agreement has been found between calculated and experimentally observed spectral properties (IR, UV-Vis, and NMR).

Synthesis and crystal structure of ((E)-{2-[(E)-(4-hydroxynaphthalen-1-yl)methylidene]hydrazin-1-yl}(methylsulfanyl)methylidene)azanium hydrogen sulfate monohydrate

In the title hydrated mol-ecular salt, C13H14N3S+·HSO4-·H2O, the protonation of the azomethine N atom in sulfuric acid medium involves the formation of the bis-ulfate anion. The mol-ecular structure of the cation is obtained from the thiol tautomer of thio-semicarbazone wherein the naphthalene moiety and the conjugation of the bonds contribute to the planarity of the mol-ecular skeleton. In the crystal, the cation, anion and water mol-ecule of crystallization are linked by a series of O-H⋯O and N-H⋯O hydrogen bonds, forming a three-dimensional network. Within this network, there are also C-H⋯π inter-actions present involving symmetry-related naphthalene rings.

Solvent-dependent dynamics of hydrogen bonding structure 5-(methylthio)-1, 3, 4-thiadiazole-2(3H)-thione as determined by Raman spectroscopy and theoretical calculation

The vibration spectra of 5-(methylthio)-1,3,4-thiadiazole-2(3H)-thione (MTTN) in acetonitrile (CH3CN), methanol (CH3OH) and water (H2O) solvents were collected and evaluated via deuterium isotopic substitution Raman spectroscopic experiments. These experiments were combined with the quantum chemical theoretical calculations using the PCM solvent model and normal mode analysis. The results confirmed that the MTTN in CH3CN, CH3OH and H2O have hydrogen bonding (H-bonding) MTTN(solvent)n clusters that produce significantly different Raman intensity patterns in different solvents. Combined with the normal Raman assignment, most resonance Raman spectra were assigned to the vibration modes of the H-bonding MTTN(CH3CN), MTTN(CH3OH)3 and MTTN(H2O)3 clusters in CH3CN, CH3OH and H2O. The theoretically-predicted frequencies and intensities in different surrounding environments enabled reliable assignments of Raman bands. The intermolecular>NH⋯O and >NH⋯N H-bonding interactions are key constituents of stable thione structures in MTTN. This underlines the significant structural differences of MTTN in CH3CN, CH3OH and H2O. H-bonding perturbation of MTTN reveal important insights about the intermolecular excited state proton transfer (ESPT) reaction mechanisms in the Franck-Condon region structural dynamics of the thione→thiol tautomer in CH3OH and H2O.

Understanding the hydrophobic mechanism of 3-hexyl-4-amino-1, 2,4-triazole-5-thione to malachite by ToF-SIMS, XPS, FTIR, contact angle, zeta potential and micro-flotation

Abstract The hydrophobic mechanism of 3-hexyl-4-amino-1, 2, 4-triazole- 5-thione (HATT) to malachite (Cu2CO3(OH)2) was investigated by contact angle, micro-flotation, zeta potential, Fourier transform infrared (FTIR) spectroscopy, time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectra (XPS). After HATT modification, the wettability of malachite surfaces was changed from hydrophilicity to hydrophobicity, and its zeta potential moved to more negative values, demonstrating that HATT might adsorb on the positively charged copper species via its anionic amino-triazole-thione group with leaving its hexyl group against malachite surfaces. The hydrophobized malachite particles attached selectively to air bubbles and subsequently moved to the pulp surface with the bubbles. FTIR and ToF-SIMS indicated that HATT might chemisorb on malachite surfaces by formation of Cu-S and Cu-N bonds with the breakage of S-H bond in HATT thiol tautomer. XPS further elucidated that a five- membered-ring HATT-Cu(I) surface complex was formed by bonding the exocyclic S and N atoms of HATT with the copper atom on malachite surfaces.

On the possibility for synthesizing dihydrotriazolothiadiazoles by condensation of 4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones with aromatic aldehydes

Regardless of the conditions, the condensation of 4-amino-2,4-dihydro-3H-1,2,4-triazole-3-thiones with aromatic aldehydes afforded the corresponding hydrazones as the only product. Both initial amines and resulting hydrazones exist as the thione rather than thiol tautomer. In no case bicyclic 5,6-dihydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles that are isomeric to the hydrazones were detected. DFT quantum chemical calculations at the B3LYP/6-31+g(d,p) level of theory with full geometry optimization showed that the hydrazone structure in methanol and DMF is more stable than the bicyclic isomer by 19–23 kcal/mol, which completely excluded the possibility for such cyclization. The thione tautomer of the hydrazones is more stable than the thiol structure by 11–13 kcal/mol.

Computational Studies for Inhibitory Action of 2-Mercapto-1-Methylimidazole Tautomers on Steel Using of Density Functional Theory Method (DFT)

The inhibition activity of thione–thiol tautomers of 2-mercapto-1-methylimidazole (MMI), namely 1-methyl-1H-imidazole-2 (3H)-thione (M1) and 1-methyl-1H-imidazole-2-thiol (M2) has been performed using density functional theory (DFT) B3LYP/6-311G (d, P) basis set level in order to elucidate the different inhibition efficiencies of these compounds as corrosion inhibitors. The calculated structural parameters correlated to the inhibition efficiency are the frontier molecular orbital energies EHOMO (Highest occupied molecular orbital energy), ELUMO (Lowest unoccupied molecular orbital energy), energy gap (ΔE), dipole moment (μ), hardness (η), softness (S), the absolute electronegativity (χ), the electrophilicity index (ω) and the fractions of electrons transferred (ΔN) from thione–thiol tautomer molecules to iron. The highest value of EHOMO is -5.30241 (eV) of M1 indicates the better inhibition efficiency than the other inhibitor M2. In our study, the trend for the (ΔEg gap) values follows the order M1>M2, which suggests that inhibitor M1 has the highest reactivity in comparison to M2 and would therefore likely interact strongly with the metal surface. The parameters like hardness (η), Softness (S), dipole moment (μ), electron affinity (EA) ionization potential (IE), electronegativity (χ) and the fraction of electron transferred (ΔN) confirms the inhibition efficiency in the order of M1>M2.

Crystal structure of a methimazole-based ionic liquid.

The structure of 1-methyl-2-(prop-2-en-1-ylsulfan­yl)-1H-imidazol-3-ium bromide, C7H11N2S+·Br−, has monoclinic (P21/c) symmetry. In the crystal, the components are linked by N—H⋯Br and C—H⋯Br hydrogen bonds. The crystal structure of the title compound undeniably proves that methimazole reacts through the thione tautomer, rather than the thiol tautomer in this system.

Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP)

Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, 1H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV–Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism.

Raman, infrared and NMR spectral analysis, normal coordinate analysis and theoretical calculations of 5-(methylthio)-1,3,4-thiadiazole-2(3H)-thione and its thiol tautomer

Raman (3400–100cm−1) and infrared (4000–200cm−1) spectra of 5-(methylthio)-1,3,4-thiadiazole-2(3H)-thione (C3H4N2S3; MTT) were measured in the solid state, and the 1H/13C NMR spectra were obtained in DMSO-d6. Initially, twelve structures were proposed as a result of thiol–thione tautomerism and the internal rotation about the C–S bonds. The energies and vibrational frequencies of the optimized structures were calculated using the 6-31G(d) basis set with the methods of MP2 and DFT/B3LYP with Gaussian 98 quantum calculations. Additionally, 1H/13C NMR chemical shifts were predicted for the thiol (structure 5) and thione (structure 9) tautomers by means of B3LYP/6-311+G(d,p) calculations utilizing the GIAO approximation and the PCM solvation model. After complete relaxation of twelve candidate isomers, the thione tautomer (structure 9) was favored owing to its low energy and its predicted real spectral frequencies. These results agree with the recorded infrared and Raman results, in addition to the observed/calculated 1H and 13C NMR spectra. Aided by normal coordinate analysis and potential energy distributions (PEDs), complete vibrational assignments have been proposed for all observed fundamentals for the thione tautomer. With the aid of MP2/6-31G(d) potential surface scans, CH3, CH3S, and SH barriers to internal rotations were estimated with the optimized structural parameters from the MP2 method with the 6-31G(d) basis set. The results are discussed herein and compared with similar model compounds whenever appropriate.

Structural and spectroscopic studies of two 1,3-benzothiazole tautomers with potential antimicrobial activity in different media. Prediction of their reactivities

In this work, the structural, electronic and vibrational properties of 6-Nitro-1,3-benzothiazole-2(3H)-thione and their 2-thiol tautomer were studied by using density functional theory (DFT) and self consistent reaction force (SCRF) calculations in gas phase and, in formamide, aqueous, DMSO and acetone solutions. The solvation energies were computed taking into account the solvent effects by using the polarized continuum (PCM) and solvation (SM) models. The atomic charges, electrostatic potentials, bond order, energy stabilizations, topological properties were calculated together with the gap energies and some descriptors in order to predict the reactivities and behaviour of both tautomers in the different media. The dipole moment and solvation energy values for both forms show different behaviours with the permittivity values of the solvents. The studies by infrared spectroscopy reveal the presence of both tautomers and of the two dimers of thione in the solid phase, as supported by the weak IR bands at 1702, 1525, 1303 and 1292cm−1 and the shoulder at 915cm−1. Moreover, the strong IR band at 3062cm−1, the bands of the media intensities at 680 and 466cm−1 and, the very weak band at 499cm−1 support the presence of the thione form. The higher electrostatic potentials on the NO2 group of the thiol tautomer and their low electrophilic index show that thiol is better electron donor than thione while, thione has the highest reactivities in all the solvents and in gas phase than thiol. Here, the complete assignments of the normal vibration modes of thione and thiol in gas phase and in the four solvents are reported for the first time.

Novel Quadruple Fluorescence Properties of Two Benzoylthiourea Isomers

Two benzoylthiourea isomers, N-2-flurobenzoy-N'-4- (N,N-dimethyl)amidophenylthiourea (2FBDAPT) and N-4-fluro-benzoy-N'-4- (N,N-dimethyl)amidophenylthiourea (4FBDAPT) were determined by fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) and X-ray diffraction. It was found that intra- and intermolecular hydrogen bonds played an important role in determining their conformations. Electronic spectra of the two compounds were investigated by UV absorption and steady-state fluorescence methods. The intermolecular hydrogen bond between the title compounds and methanol molecules caused the long wavelength absorption bands in methanol to weaken and vanish indeed. Quadruple fluorescence bands in ultraviolet and visible region were observed in the studied solvents upon the variable excitation wavelength. As same as Azumaya's suggestions for benzanilide (BA), F4 fluorescence bands with the maximum wavelength (λ(max)) between 546 nm and 622 nm were characteristic of TICT fluorescence. F3 bands of λ(max) from 434 nm to 483 nm were explained by the ESIPT model of the S1 state of the thiol tautomer to the S1 state of the keto tautomer. The new proposition was that F2 bands with λ(max) at about 365 nm were attributed to ESIPT from the S1 state of the thiol tautomer to the S0 state of the enol tautomer. And F1 fluorescence emissions with λ(max) at about 310 nm originated from the local S1 transitions of the enol tautomer. All experimental results were supported by MP2, CASSCF and CASPT2 quantum chemical calculations.

Adsorption of mercaptobenzoheterocyclic compounds on sulfide mineral surfaces: A density functional theory study of structure–reactivity relations

Mercaptobenzoheterocyclic compounds: 2-mercaptobenzothiazole (MBT), 2-mercaptobenzoxazole (MBO) and 2-mercaptobenzimidazole (MBI) are widely used as corrosion inhibitors and flotation collectors, but the true nature of the adsorption selectivity and activity to solid surfaces is still unclear. Using density functional theory (DFT) calculations, this study investigates the structure–reactivity relation of MBO, MBI and MBT as flotation collectors with sulfide minerals. The results demonstrate that the O, N and S heteratoms in MBO, MBI and MBT molecules can attend the chemical bond formation with metal atoms on mineral surfaces and significantly impact the chemical reactivity of these mercaptobenzoheterocyclic compounds, and the reactive power of the three compounds to metal and mineral surfaces is predicted to be MBT>MBI≥MBO. In addition, the chemical reactivity of the thione, thiol and ionized thiol species of these mercaptobenzoheterocyclic compounds in both vacuum and aqueous phases is also studied. The results show that the thione tautomers of MBO, MBI and MBT is more stable and reactive than their thiol tautomers, and in aqueous solutions, the ionized thiol exhibits the strongest reactivity. The theoretical results of structure–reactivity relations provide an atomic level understanding of the activity and selectivity observed by the experimental investigation of the adsorption of MBO, MBI and MBT on metal and sulfide surfaces. The further pyrite flotation tests indicate that MBT has the highest collecting power to pyrite, followed by MBI and then MBO, which is consistent with the theoretical prediction.

Theoretical and experimental study on the reaction route for the FVP of 2-thioxohexahydroquinazolinones

Structural and conformational analyses through the use of different spectrometric techniques as well as DFT calculations performed to analyze the results of FVP reactions on pure cis as well as pure trans 2-thioxo-hexahydroquinazolinones yielding isothiocyanates as main products have been carried out. With these, we could assess the specific tautomer/isomer/conformer that produces the products in each FVP reaction. It was confirmed that for both isomers, the reaction takes place from the thiol tautomer, and for the special case of the cis isomer, the conformer involved is the N(1)-in.

The cycloauration of pyridine-2-thiocarboxamide ligands

2-Pyridine thiocarboxamides 2-(C 5 H 5 N)C(S)NHR (R = p -C 6 H 4 Me, CH 2 Ph, Me, p- C 6 H 4 OMe) undergo direct cycloauration with H[AuCl 4 ]; the deprotonated ligand coordinates via the pyridyl nitrogen and sulphur atom. The ligand with R = 2-pyridyl reacted differently; instead of cycloauration, the ligand was oxidised to give a heterocyclic 1,2,4-thiadiazolo[2,3- a ]pyridinium ring. Reactions of H[AuCl 4 ] with N -substituted 2-pyridine thiocarboxamide ligands 2-(C 5 H 4 N)C(S)NHR (R = p -C 6 H 4 Me, CH 2 Ph, Me, p -C 6 H 4 OMe) gave cycloaurated derivatives {(C 5 H 4 N)C(S)NR}AuCl 2 , with the ligand bonded as the thiol tautomer through the deprotonated SH group and the pyridine N atom to give a five-membered metallacyclic ring. The X-ray structure determination of the R = CH 2 Ph derivative shows a square–planar gold(III) complex that dimerises in the solid state by weak Au···S intermolecular interactions. In contrast, in the reaction of H[AuCl 4 ] with 2-(C 5 H 4 N)C(S)NHR where R = 2-pyridyl, the ligand was oxidised to give a 1,2,4-thiadiazolo[2,3- a ]pyridinium heterocyclic ring that was crystallographically characterised.

UV‐induced transformations of matrix‐isolated 1,3,4‐thiadiazole‐2‐thiones

AbstractMonomers of 5‐mercapto‐1,3,4‐thiadiazole‐2‐thione (bismuthiol) were studied using an experimental matrix‐isolation technique as well as by carrying out theoretical quantum chemical calculations. The calculations, performed using the quadratic configuration interaction method with single and double excitations (QCISD)/6‐31++G(d,p)//DFT(B3LYP)/6‐311++G(2d,p), predict that the thione–thiol tautomer of bismuthiol should be significantly (by more than 19 kJ mol−1) more stable than other tautomeric forms. Accordingly, only the signatures of the thione–thiol tautomer were observed in the FT‐IR spectrum of bismuthiol, recorded directly after deposition of an Ar matrix. UV (λ > 320 nm) irradiation induced the conversion of the thione–thiol tautomer into the dithiol form. Analogous investigations were carried out for two related compounds: 5‐methyl‐1,3,4‐thiadiazole‐2‐thione and 5‐methylthio‐1,3,4‐thiadiazole‐2‐thione. For these two species, only the thione tautomeric forms were observed after deposition of Ar matrices. These tautomers were predicted (by QCISD calculations) to be more stable (by at least 19 kJ mol−1) than other tautomeric forms. Upon UV irradiation, the most stable thione forms of these compounds were transformed into the corresponding thiol tautomers. Direct observation of the thione → thiol phototautomeric processes provides a clear proof that intramolecular proton transfer reaction can occur in molecules, such as bismuthiol, in spite of the increased NH···S distance, in comparison to other phototautomerizing species studied so far. All the isomers of the studied compounds (substrates and products of the photoreactions) were identified by comparison of their IR spectra with the spectra calculated at the DFT(B3LYP)/6‐311++G(2d,p) level of theory for possible isomeric structures. Copyright © 2009 John Wiley & Sons, Ltd.

Intramolecular heterocyclization of α,β-unsaturated ketone thiosemicarbazones

Intramolecular heterocyclization of thiosemicarbazones derived from α,β-enones under acid activation of one nucleophilic center afforded previously unknown 2-(2-arylethenyl)-2,3-dihydro-1,3,4-thiadiazoles. The transformation involves the thiol tautomer of thiosemicarbazone without participation of the conjugated carbon-carbon double bond.

Synthesis and theoretical characterization of some new 4-substituted-1,3-diphenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazoles with potential pharmacological activity

Synthesis of some new triazoles fused to triazoles 5a–c or thiadiazoles 6a–c and the thiol-thione tautomeric equilibrium study of the title compounds are reported. The “rule of five” and complementary criteria of pharmacokinetic properties were determined to predict whether these compounds are orally bioavailable. Semiempirical parameterizations have been critically benchmarked for the thiol-thione tautomeric equilibrium against the DFT calculations. It was shown that unlike the AM1 and PM3 Hamiltonians, which erroneously predict higher stability of the thiol tautomer, the newly developed RM1 Hamiltonian, on the other hand, predicts energetics of this equilibrium in excellent agreement with the DFT results. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:713–718, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20499

X-ray crystallographic and theoretical study of 4-cyclohexyl-5-(2-furyl)-2,4-dihydro-3 H-1,2,4-triazole-3-thione

In order to investigate the molecular geometry, structural analysis of the title compound ( 4a) was carried out by single crystal X-ray diffraction. Tautomeric properties and conformations were investigated by semi-empirical (AM1) and ab initio quantum mechanical (RHF/6-31G) calculations. The compound prefers thione tautomer in the solid state. On the other hand, semiempirical calculations show that in the gas phase the thiol tautomer is energetically favored in most cases.

Density functional study of the conformations and intramolecular proton transfer in thiohydroxamic acids

The conformational preferences of thiohydroxamic acids (N-hydroxythioamides) are investigated by the density functional B3LYP/6-311++G(3df,3pd)//B3LYP/6-31G(d) method in this work. Unlike hydroxamic acids, the thione and thiol forms are found to be equally stable in the gas phase, and the reaction pathways for the interconversion between the thione and thiol forms have been deduced to involve rotation about the C[double bond, length as m-dash]N bond of the thiol tautomer in the rate-determining step. The effect of aqueous solvation on the reactions has also been investigated. It is found that inclusion of a few explicit water molecules in an implicit solvent calculation is necessary in order to accurately account for hydrogen bonding effects. Thiohydroxamic acids, like their hydroxamic acid analogues, are found to be N-acids, both in the gas phase and in aqueous solution.