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.     

A practical synthesis and spectroscopic study of new potentially biologically active S-lithocholic acid-substituted derivatives of 2-thiouracil

Five new S-3α-acetoxy-5β-lithocholic acid methyl ester-substituted derivatives of 2-thiouracil and 6-methyl-2-thiouracil have been prepared. 5-Morpholino-methyl-2-thiouracil, 5-piperidinomethyl-2-thiouracil, and 5-(4-methylpiperidino)methyl-2-thiouracil have been obtained via the Mannich reaction between 6-methyl-2-thiouracil, paraformaldehyde, and the cyclic secondary amines morpholine, piperidine, or 4-methylpiperidine in ethanol. The structures of the compounds were confirmed by spectral (¹H NMR, ¹³C NMR, and FT-IR) analyses and mass spectrometry. Estimation of the pharmacotherapeutic potential has been accomplished for the synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS).     

N- vs. S-PTC Alkylation of 5-Carboethoxy-2-thiouracil And Its Reactivity Towards Some Nucleophilic Reagents

The reactivity of 5-carboethoxy-2-thiouracil (1) toward alkylation by different organohalogen compounds under phase-transfer catalysis (PTC) conditions has been investigated to give S-monoalkylated products and/or simultaneous S- and N-dialkylated products. Also, nucleophilic additions of methylmagnesium iodide, hydroxylamine, and hydrazine to 5-carbethoxy-2-thiouracil (1) have been investigated. The structures of all products have been confirmed by elemental analysis and spectral data.     

Theoretical Studies on the Binding of Cd~（2＋） to Uracil and Its Thio-derivatives

The interaction of Cd2+ with uracil,2-thiouracil,4-thiouracil and 2,4-dithiouracil have been investigated by the density functional theory(DFT) calculations.For uracil and 2,4-dithiouracil,where the two basic sites are the same,Cd2+ attachment to the heteroatom at position 4 is preferred.However,for the systems where both types of basic centers,a carbonyl and a thiocarbonyl groups,are present,Cd2+ association with sulfur is favorable.The enhanced stability of these enolic and thiol forms comes from Cd2+ interaction with two basic sites simultaneously,which thereby triggers a significant aromatization of the ring.More significantly,the Cd2+ binding energy with uracil and its thio-derivatives is larger than the tautomerization barriers connecting the diketo-like forms with the corresponding enolic-like tautomers.Consequently,when associated with Cd2+,all tautomers are energetically accessible and should be observed in the gas phase.     

Electrochemical oxidation of 2-thiouracil at pyrolytic graphite electrode

2-Thiouracil has been studied in phosphate buffers of pH 1.95-11.08 using linear and cyclic sweep voltammetry, coulometry, controlled potential electrolysis and spectral studies. One well-defined oxidation peak I(a) in the pH range 1.95-11.08 was noticed. The number of electrons involved in peak I(a) was found to be four in a thin layer cell whereas under exhaustive electrolysis condition oxidation was found to involve six electrons. A reduction peak II(c) (2e, 2H(+)) is noticed in the reverse sweep. Spectral studies during oxidation were carried out at different pH. Kinetic studies indicated that the decay of the UV-absorbing intermediate is a first order reaction. The products of the electrooxidation have been characterized and a tentative EC mechanism has been suggested for the oxidation of 2-thiouracil.     

Unimolecular photochemistry of 4-thiouracils

Unimolecular phototautomeric reactions in 4-thiouracil, 1-methyl-4-thiouracil and 6-aza-4-thiouracil were studied using the matrix-isolation technique combined with infrared absorption spectroscopy. For monomers of these compounds, isolated in solid argon at 10 K, an intramolecular proton-transfer photoreaction was observed. Upon UV (lambda > 345 nm) irradiation, the initial oxo-thione forms of 4-thiouracils were converted into the corresponding oxo-thiol tautomers. The photogenerated oxo-thiol isomers were identified by comparing their experimental IR spectra with the spectra theoretically calculated at the DFT(B3LYP)/6-311++G(2d,p) level. Good agreement between the observed and predicted pattern of spectral bands allowed a reliable identification. This is the first report on experimental observation of isomeric forms of 4-thiouracils other than the canonical oxo-thione tautomers.     

A practical synthesis of new S,N-disubstituted derivatives of 5-(4-methylpiperidino)methyl-2-thiouracil

5-(4-Methylpiperidino)methyl-2-thiouracil (1) has been obtained via the Mannich reaction between 2-thiouracil, paraformaldehyde, and a cyclic secondary amine such as 4-methylpiperidine (4-MP) in ethanol. New S,N(1)-di-o-(m- and p-)bromo-(nitro-) benzyl-substituted derivatives have been synthesized successfully in the reactions of 1 with the corresponding o-(m- and p-)bromobenzyl bromides or o-(m- and p-) nitrobenzyl chlorides in DMF solution in the presence of K₂CO₃. The opposite method of synthesis, that is, the reaction between 2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyluracils and 2-o-(m- and p-)nitrobenzylthio-1-o-(m- and p-) nitrobenzyluracils (8), with paraformaldehyde and 4-methylpiperidine in ethanol failed, indicating the important role of the enol form of 2-thiouracil for the Mannich reaction to be successful.     

Chelate adsorption for trace voltammetric measurements of 2-thiouracil and 4-thiouridine

A very sensitive electrochemical stripping method for trace measurements of 2-thiouracil and 4-thiouridine in presence of Cu(II) is described. The chelate of Cu(II) with 2-thiouracil and 4-thiouridine is adsorbed on the hanging mercury drop electrode, and the reduction current of the accumulated complex is measured by cathodic stripping voltammetry. The adsorption and redox behaviour are indicated by cyclic voltammetry. Optimum experimental conditions include a preconcentration potential of 0.0 V, solution of pH 7.2, adsorption time 5 min, pulse amplitude 100 mV, and a linear scan mode. The sharp chelate peak, associated with the effective interfacial accumulation, coupled with the flat baseline, facilitates measurements at the nanomolar and submicromolar concentration levels.     

Influence of cationic gemini surfactants on the electrochemical behavior of 2-thiouracil at silver electrodes

The voltammetric behavior of 2-thiouracil at a silver electrode is described. 2-Thiouracil can deposit or chemisorb anodically at silver surface; when the potential is made more negative the deposited 2-thiouracil undergoes reductive desorption-process, yielding a cathodic peak at about −1.2 V (vs. SCE) in basic phosphate buffer solution (pH 10.3). In the presence of cationic gemini surfactant C₄H₈–1,4-(C₁₆H₃₃N⁺ (CH₃)₂Br⁻)₂ (C₁₆–C₄–C₁₆) the deposition of 2-thiouracil is greatly improved and the cathodic peak is enhanced. Meanwhile, the peak shifts to more negative potential. The role of C₁₆–C₄–C₁₆ is thought to combine and coadsorb with 2-thiouracil at silver surface as well as reduce the electrostatic repulse in the deposited film, thus making it more easy to deposit and desorb at more negative potential. With C₁₆–C₄–C₁₆ the lateral interaction of deposits reduces, the reductive desorption becomes faster and the cathodic peak becomes sharper. For geminis with different spacer groups and alkyl chains, their influence is mainly determined by their hydrophobicity and adsorbability. It was found that increasing length of alkyl chain was favorable for obtaining a high and sharp desorption peak, whose peak potential is more negative. For comparison, surfactants with single alkyl-chain and double alkyl-chain, such as cetyltrimethyl ammonium bromide and dicetyldimethyl ammonium bromide were studied. They made the desorption peak shift less due to their weaker combination with 2-thiouracil.     

UV-induced generation of rare tautomers of 2-thiouracils: a matrix isolation study

Unimolecular photoisomerization reactions were studied for 2-thiouracil, 6-aza-2-thiothymine, 1-methyl-2-thiouracil, and 3-methyl-2-thiouracil isolated in low-temperature Ar matrixes. The IR spectra have revealed that before UV irradiation all the matrix-isolated compounds adopted exclusively the oxo-thione tautomeric form. Upon UV (lambda > 320 nm) irradiation of the matrixes, two oxo-thiol photoproducts were generated for monomeric 2-thiouracil as well as for monomeric 6-aza-2-thiothymine. Generation of these products corresponds to transfer of a proton from either the N(1)-H or N(3)-H group to the sulfur atom of the C(2)=S thiocarbonyl moiety. The first of the above reactions was photoreversible. As a consequence, after prolonged UV irradiation most of the material was transformed into the oxo-thiol-N(1)H form. The hydroxy-thiol tautomers of 2-thiouracil and 6-aza-2-thiothymine were also photogenerated as minor products. For 1-methyl-2-thiouracil and 3-methyl-2-thiouracil, thione --> thiol phototautomeric reactions yielded the oxo-thiol isomers of the compounds. Since these reactions were photoreversible, the final stages of the photoinduced processes corresponded, for both methylated 2-thiouracils, to photostationary states. All the products of the investigated photoreactions were identified by comparison of their IR spectra with the spectra calculated at the DFT(B3LYP)/6-311++G(2d,p) level.     

Electrochemical oxidation of catechol in the presence of 2-thiouracil: application to electro-organic synthesis

The electrochemical oxidation of catechol in the presence of 2-thiouracil (as a nucleophile) has been studied in aqueous solutions using cyclic voltammetry and controlled-potential coulometric techniques. The results indicate that catechol participating in a 1,4 (Michael) addition reaction converts to a new thiadiazafluorenone compound. The electrochemical synthesis of this compound has been successfully performed in an undivided cell in a good yield and purity and was characterized by IR, ¹H and ¹³C NMR, mass spectrometry and elemental analysis.     

Preparation of [76Br] 5-bromo-2-thiouracil, a positron-emitting melanoma localizing agent

Derivatives of 2-thiouracil are known to incorporate into the growing melanin pigment of melanomas as false melanin precursors. Animal and pilot patient studies have demonstrated, that radioiodinated 5-iodo-2-thiouracil is a promising agent for visualization of melanotic melanomas. In this study, 2-bromo-2-thiouracil was labeled using the positron-emitting isotope ⁷⁶Br (T _1/2 = 16.2 h), which potentially enables to use such advantages of PET as superior spatial resolution and possibility to quantify radioactivity concentration in vivo. The use of Chloramine-T as oxidant provided a labeling efficiency of about 70%.     

H2, N2, CO, and CO2 sorption properties of a series of robust sodalite-type microporous coordination polymers

H2, N2, CO, and CO2 are readily incorporated in the porous, 3D sodalitic frameworks of coordination polymers of the [ML2]n type, with M = Pd(II) or Cu(II) and HL = 2-hydroxypyrimidine or 4-hydroxypyrimidine. The metal ion and ligand functionalization modulate their sorption properties, making these materials suitable for gas storage and separation purposes.     

A novel approach for simultaneous determination of 2-mercaptobenzimidazole and derivatives of 2-thiouracil in animal tissue by gas chromatography/mass spectrometry

A novel approach for determination of 2-mercaptobenzimidazole (MBI) and other thyreostatic residues in animal tissues by gas chromatography/mass spectrometry (GC/MS) in selected ion monitoring mode was developed. The analytes in animal tissues (including hypothyroid, pork muscle and beef samples) were extracted by acetonitrile, and then purified by a matrix solid-phase dispersion (MSPD) procedure after the extraction residues had been dissolved in water. The thyreostatic residues were derivatized by pentafluorobenzyl bromide (PFBBr) under strong basic conditions and then N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) before GC/MS analysis. Different kinds of solid supports with various polarities for the MSPD procedure were investigated, and it was found that silica gel was suitable for the purpose. The average recoveries of the thyreostatic drugs in animal tissues ranged from 71.5-96.9% with the relative standard deviations below 10%. By using the developed method, the limits of detection were 10 microg/kg for MBI; 5 microg/kg for 6-phenyl-2-thiouracil; and 2 microg/kg for 2-thiouracil, 6-methyl-2-thiouracil and 6-propyl-2-thiouracil. The stability of the thyreostatic drugs in spiked animal tissues was tested, and the results showed that the thyreostatic drugs did not decompose within 3 months if the sample was stored in darkness below -20 degrees C.     

Reaction of 2-thiouracil with carboxylic acid 1,2,2,2-tetrachloroethylamides

Amidoalkylation of 2-thiouracil with 1,2,2,2-tetrachloroethylamides in the presence of triethylamine or sodium hydroxide gives products of S-, O-, and N-substitution, depending on the reaction conditions.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 95–100, January, 1992.     

Photoelectron spectroscopic study of the negative ions of 4-thiouracil and 2,4-dithiouracil

We report the photoelectron spectra of the negative ions of 4-thiouracil (4-TU)(-) and 2,4-dithiouracil (2,4-DTU)(-). Both of these spectra are indicative of valence anions, and they are each dominated by a single broad band with vertical detachment energies of 1.05 and 1.4 eV, respectively. Complementary calculations by Dolgounitcheva, Zakrzewski, and Ortiz (see companion paper) are in accord with our experimental results and conclude that the (4-TU)(-) and (2,4-DTU)(-) anions, reported herein, are valence anions of canonical 4-thiouracil and canonical dithiouracil. Comparisons among the anions and corresponding neutrals of 4-thiouracil, 2,4-dithiouracil, 5-chlorouracil, 5-fluorouracil, and uracil itself show that both sulfur and halogen modifications of uracil give rise to significant changes in the electronic structure. The electron affinities of the first four are all substantially larger than that of the canonical uracil.     

DFT studies on the favored and rare tautomers of neutral and redox cytosine

The complete tautomeric mixture consisting of nine prototropic tautomers has been studied in the gas phase at the DFT(B3LYP)/6-311+G(d,p) level for neutral, oxidized, and reduced cytosine. Rotational isomerism of the exo –OH group and geometrical isomerism of the exo =NH group have also been considered. Tautomeric conversions possible for cytosine have been compared with those for its structural models, 4-amino- and 2-hydroxypyrimidine. Effects of intramolecular interactions between neighboring groups for cytosine are analogous to those observed for model compounds. Although they are not very strong, they are sufficient to influence tautomeric equilibria and relative stabilities of individual tautomers. One-electron oxidation and one-electron reduction change tautomeric preferences. Tautomers that are rare forms for neutral cytosine become favored ones for oxidized and reduced cytosine. Aromaticity is not the main factor that dictates the tautomeric preferences. Stability of functional groups seems to be more important than full electron delocalization.     

Polycondensation of 6-methyl-2-thiouracil by the action of p-nitrophenyldiazonium tetrafluoroboride and cupric chloride

Conclusion The reaction of 6-methyl-2-thiouracil with p-nitrophenyldiazonium tetrafluoroboride in the presence of CuCl₂·2H₂O yielded a 14 cooligomer of 6-methyl-2-thiouracil and 6-methyluracil.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1342–1344, June, 1982.The authors express their gratitude to G. I. Timofeeva and L. A. Lopanova for molecular weight determinations.     

Synthesis of pyridinylketones, and their cyclic derivatives produced from 6-methyl-2-thiouracil

A possibility to obtain pyrimidines, containing oxoalkyl moiety in 2 position of the ring from the available 6-methyl-2-thiouracil was shown.     

Surface enhanced Raman spectroscopy analysis of the adsorption of 2-thiouracil to Au,Ag and Cu electrodes: Surface potential dependence

Surface enhanced Raman spectroscopy has been used to study the potential controlled behavior of 2-thiouracil adsorbed on silver, gold and copper electrodes. Comparison of the normal Raman and SER spectra shows that the molecule adsorbs chemically to the metallic surfaces through its deprotonated sulfur atom. The position of the molecular aromatic ring in respect to the surface normal under potential modulation was analyzed using the electromagnetic theory's selection rules. Our data indicate that for all electrodes the surface potential induces a molecular reorientation leading to a more upright or tilted position.