Parent Thiophene Research Articles

Targeting Carbohydrate Mimetics of Tetrahydrofuran-Containing Acetogenins to Prostate Cancer.

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa.

On the protonation and deuteration of 2-methylmercaptothiophene: Formation of a 2′,3′-dihydro-2,3′-bithiophene dimer

2‑Methylmercaptothiophene as heterocyclic thioanisole analogue is transformed by dissolving in trifluoracetic acid, instead into a S or C protonated species, into a dimeric compound with a tetrahydrothiophene unit. This finding has been derived from appropriate 1H NMR and mass spectra and stands in analogy to the oligomerisation of the parent thiophene with polyphosphoric acid.

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.

Templated Ring-Opening Metathesis (TROM) of Cyclic Olefins Tethered to Unimolecular Oligo(thiophene)s

We developed a fully abiotic approach to template the synthesis of discrete unimolecular polyolefins. Discrete, unimolecular oligo(thiophene)s with alternating sequence were obtained by iterative convergent/divergent couplings and then functionalized with pendant cyclic olefin monomers in the side chains. Upon treatment with the Grubbs third-generation catalyst in dilute solution (0.15 mM in DCM at 0 °C), the pendant monomers undergo templated ring-opening metathesis (TROM). Then, the daughter olefin is liberated from the parent thiophene by hydrolysis. Cyclooctenes undergo TROM to afford macrocyclic products that exactly replicate the chain length of the parent oligomer, as evidenced by MALDI MS/MS and NMR. Norbornene derivatives also undergo TROM and replicate unimolecular chain lengths, but in contrast, they exclusively form the linear oligomeric products with styrenic end groups. A template that was functionalized with one norbornene unit at the α chain end, followed by five cyclooctene units along th...

Redox-Driven Ion Exchange of Poly(3,4,-ethylenedioxythiophene) Films in Deep Eutectic Solvents

Poly(3,4-ethylenedioxythiophene) (PEDOT) is one of a range of conducting polymers based on aromatic heterocyclic monomers, typified by thiophene, pyrrole and their derivatives. The substitution pattern in PEDOT has the dual advantages of shifting the potentials for polymerization and redox switching into a more convenient range (as compared to the parent thiophene) and of blocking attack at the 3- and 4- positions of the aromatic ring. Both of these attributes enhance its practical application for energy storage applications, such as batteries and supercapacitors.Quite generally, the rates of doping and undoping (charging and discharging, in the context of energy storage) of conducting polymers are limited not by the rate of electron transport along the polymer backbone, but by the transport rate(s) of the charge balancing ion(s), i.e. dopant(s). The dynamics of these processes have been widely studied during redox switching of PEDOT films immersed in diverse electrolyte media based on molecular solvent systems. Although the quantitative details vary with the electrolyte selected, the qualitative outcome is that anion transfer is commonly the dominant process accompanying PEDOT oxidation (p-doping), but that cation transfer (in the opposite direction) can be appreciable, and in any case solvent transfer is significant; in the context of nanogravimetric measurements (using the EQCM), the ion and neutral molecule transfers can be distinguished according to their correlation with transferred charge. Measurements of the absolute solvent population (cf. changes measured in an EQCM experiment) in many conducting polymer films reveal that this may represent ca. 50% by volume of the film: this facilitates both ion transfers and polymer spinal motions. While such studies have revealed many interesting phenomena, notably solvation-controlled viscoelastic phenomena, a number of limitations make conventional solvent media unsuitable for practical applications; these may include available potential window, safety, toxicity or flammability. This motivates research on the redox chemistry of electroactive polymers in novel media, such as room temperature ionic liquids. Amongst these, we have been exploring the properties of deep eutectic solvent (DES) media based on various formulations of quaternary ammonium salts (QAS), hydrogen bond donors (HBD) and metal salts, in which complexation chemistry amongst the components generates fully ionic media. From a practical perspective, this provides an essentially unlimited source of ions (dopant). From a fundamental perspective, the dramatic difference is that these fully ionic media contain no solvent to plasticise the polymer; the more subtle difference is that the question of permselectivity that prevails (or fails) at low (or high) electrolyte concentration in a conventional solvent-based medium now becomes redundant.Here we describe nanogravimetric acoustic wave (EQCM) studies of redox driven ion transfers for PEDOT films exposed to three DES formulations variously involving choline chloride (Ch+Cl-) as the QAS, ethylene glycol (EG) as the HBD and ZnCl2 as the metal salt. Viscosity effects associated with the DES are significant but, via acoustic admittance measurements, one can obtain film ion population change data. These are presented as a function of timescale (potential scan rate in a voltammetric experiment) for potentiostatically- and potentiodynamically-grown PEDOT films subsequently exposed to ZnCl2/EG, ZnCl2/acetamide and ZnCl2/Ethaline (where Ethaline is a 1:2 stoichiometric mixture of Ch+Cl- and EG). Significantly, for thicker films (consistent with practical applications), there is incomplete charge recovery at faster scan rates, with accompanying failure to restore the initial film ion composition. In multi-cycling experiments this leads to evolution of response; we discuss re-equilibration when the film is subsequently held in a resting state. Cycling over prolonged time intervals also results in evolution of film responses. The fundamental interpretation and practical consequences of these observations will be discussed.We thank EU FP7 for financial support (NMP3-SL-2008-226655)

Effect of electron-withdrawing side chain modifications on the optical properties of thiophene–quinoxaline acceptor based polymers

Four new thiophene–quinoxaline acceptor based polymers have been synthesized. The parent thiophene–quinoxaline acceptor based copolymer was modified by introducing different electron-withdrawing groups adjacent to the thiophene side group. The effect on the physical, electrochemical and optical properties of the polymer series is discussed with respect to the parent thiophene–quinoxaline acceptor based polymer. The side chain carbonyl from one modified monomer could conveniently be transformed to either a difluoromethylene or an -ylidene malononitrile group via carbonyl transformations. For all polymers incorporating an electron-withdrawing side group both the HOMO and especially the LUMO were significantly shifted away from vacuum while all exhibit enhanced light harvesting ability. Especially the incorporation of an -ylidine malononitrile side group increases both the spectral coverage and absorption coefficient. Incorporation of a difluoromethylene side group resulted in a twofold increase of the molecular weight compared to the parent polymer structure.

Theoretical study on charge transport properties of cyanovinyl-substituted oligothiophenes

When the oligothiophene is substituted by dicyanovinyl (DCV) or tricyanovinyl (TCV) group, how does its transport property change? Here, we will mainly focus on exploring the influence on charge transport properties of introducing a strong electron-withdrawing DCV/TCV group to the thiophene units within Marcus–Levich–Jortner formalism at the level of density functional theory. The results show that the introduction of cyanovinyl-substituents improves the molecular π-stacking, decreases the frontier molecular orbital energy levels and reorganization energies, and increases the transfer integrals and mobilities, comparing with their parent thiophene molecules. It is interesting to find the phenomenon that enriching intermolecular interactions can be favorable for controlling the transport channel and thus get high mobility, which would be shown by the angular resolution anisotropic mobilities analysis. Besides, the simulated packing motifs of dimers for 3a and 3b without crystal structures reported indicate that their packing may form the slip π–π stacking, and that 3b may be a good ambipolar material. In a word, compared with corresponding thiophene analogues and tetracyanoquinodimethane, these compounds may become the candidates for the n-type or ambipolar organic semiconductor materials.

Dioxygenase-catalysed oxidation of monosubstituted thiophenes: sulfoxidation versus dihydrodiol formation.

Toluene dioxygenase (TDO)-catalysed sulfoxidation, using Pseudomonas putida UV4, was observed for the thiophene substrates 1A-1N. The unstable thiophene oxide metabolites, 6A-6G, 6K-6N, spontaneously dimerised yielding the corresponding racemic disulfoxide cycloadducts 7A-7G, 7K-7N. Dimeric or crossed [4 + 2] cycloaddition products, derived from the thiophene oxide intermediates 6A and 6D or 6B and 6D, were found when mixtures of thiophene substrates 1A and 1D or 1B and 1D were biotransformed. The thiophene sulfoxide metabolite 6B was also trapped as cycloadducts 17 or 18 using stable dienophiles. Preferential dioxygenase-catalysed oxidation of the substituent on the thiophene ring, including exocyclic sulfoxidation (1H-1J) and cis-dihydroxylation of a phenyl substituent (1G and 1N), was also observed. An enzyme-catalysed deoxygenation of a sulfoxide in P. putida UV4 was noticed when racemic disulfoxide cyclo-adducts 7A, 7B and 7K were converted to the corresponding enantioenriched monosulfoxides 8A, 8B and 8K via a kinetic resolution process. The parent thiophene 1A and the 3-substituted thiophenes 1K-1N were also found to undergo ring dihydroxylation yielding the cis/trans-dihydrodiol metabolites 9A and 9K-9N. Evidence is provided for a dehydrogenase-catalysed desaturation of a heterocyclic dihydrodiol (9Kcis/9Ktrans) to yield the corresponding 2,3-dihydroxythiophene (24) as its preferred thiolactone tautomer (23). A simple model to allow prediction of the structure of metabolites, formed from TDO-catalysed bacterial oxidation of thiophene substrates 1, is presented.

1-Oxides and 1,1-Dioxides of Thiophenes and Selenophenes and Related Compounds

Abstract The first topic of the present article involves recent advances in the chemistry of thiophene 1-oxides. Next is the chemistry of the parent thiophene 1,1-dioxide, which is followed by that of congested thiophene 1,1-dioxides, where emphasis is placed on their syntheses and synthetic applications. The chemistry of 1-imino, 1,1-diimino, and 1-imino-1-oxo derivatives of thiophenes is then described. Finally, the newborn chemistry of selenophene 1-oxides and 1,1-dioxides is discussed.

Synthesis and Properties of the Parent Thiophene 1,1-Dioxide

Thiophene 1,1-dioxides are synthetically and theoretically important compounds which act as 2π- or 4π-components in a range of cycloadditions. Our recent exhaustive literature survey has revealed that more than 300 papers had appeared on the chemistry of thiophene 1,1-dioxides. Among them, at least 33 papers have described the chemistry of the parent thiophene 1,1-dioxide (1) theoretically or experimentally. However, despite such enormous efforts, 1 has eluded isolation most likely as a result of a rapid cyclodimerization process. Thus, most of the evidence for its existence comes from chemical trapping experiments. We report here the synthesis, isolation, and full characterization of 11 and its monosubstituted derivatives.

Thiophene 1,1-Dioxide: Synthesis, Isolation, and Properties

Abstract Oxidation of thiophene with dimethyldioxirane at −20 °C and removal of the solvent and volatile materials below −40 °C allowed the isolation of the parent thiophene 1,1-dioxide (1) as colorless crystals in pure form. The 1,1-dioxide 1, which had eluded isolation for a long time despite many efforts, melted at about 6 °C and the melt solidified at room temperature because of the dimeric and trimeric products formation. The structure of 1 was fully characterized by 1H- and 13C NMR, IR, Raman, UV/vis, and Mass spectroscopies. The decomposition of 1 in solution provided the dimer (7) as the principal product along with the trimer (9), whereas the decomposition of a neat sample furnished 7 and 9 in comparable amounts. The half-life of 1 is dependent upon the concentration of 1; 137 and 747 min at 25 °C in 0.12 and 0.025 M CDCl3 solutions (1 M = 1 mol dm−3), respectively. Kinetics of the dimerization of 1 in a dilute solution provided the activation parameters of Ea = 64.4 (±0.3) kJ mol−1, ΔH≠ = 62.0 (±0.3) kJ mol−1, and ΔS≠ = −59.8 (±1.0) J K−1 mol−1. Attempted reactions of 1 with a series of dienophiles and dienes all failed because the dimerization of 1 is much faster than reactions with these additives. An exception is the reaction with cyclopentadiene which gave the Diels–Alder adduct in good yield. The adduct of the dimer 7 with dimethyl acetylenedicarboxylate was found to undergo a retro Diels–Alder reaction to regenerate 1.

Synthesis and Properties of the Parent Thiophene 1,1-Dioxide

Thiophene 1,1-dioxides are synthetically and theoretically important compounds which act as 2π- or 4π-components in a range of cycloadditions. Our recent exhaustive literature survey has revealed that more than 300 papers had appeared on the chemistry of thiophene 1,1-dioxides. Among them, at least 33 papers have described the chemistry of the parent thiophene 1,1-dioxide (1) theoretically or experimentally. However, despite such enormous efforts, 1 has eluded isolation most likely as a result of a rapid cyclodimerization process. Thus, most of the evidence for its existence comes from chemical trapping experiments. We report here the synthesis, isolation, and full characterization of 11 and its monosubstituted derivatives.

Hydrous pyrolysis reactions of sulphur in three Australian brown coals

Hydrous pyrolysis of three Australian brown coals in the presence of cadmium acetate (CdOAc) indicates that as much as 77% of the original organic sulphur may be generated as H 2S. In the absence of CdOAc much of the generated H 2S was re-adsorbed back into the insoluble coal residues. GC–MS analyses of the solvent extracts of the coals and of the solvent extracts of the hydrous pyrolysates at 110–330°C both in the presence and absence of cadmium acetate reveal a little parent thiophene and benzothiophene totally dominated by a broad range of methyl derivatives. Yields of these sulphur compounds tend to be greater when cadmium acetate is absent. Benzothiophenes are favoured over thiophenes at the higher hydrolysis temperatures. Analyses of the solvent extracted residues by FP–GC–MS and of mixtures of low sulphur coal and elemental sulphur, produced a similar range of parent thiophene and benzothiophene and their methylated derivatives. The ubiquity of these sulphur compounds suggests these to be the thermodynamically favoured products of sulphur/organic matter interaction. The only other class of sulphur compounds seen, the longer chain n-alkyl thiophenes, occurred in the soluble 200°C hydrous pyrolysis products obtained in the absence of cadmium acetate. Only these appear to reflect structures in the original brown coals. The implication of this study is that the earliest formed organic sulphur compounds in immature sediment will, with increasing temperature, continue to decompose and release H 2S and elemental sulphur. The released sulphur species will, in turn, undergo reaction with the organic matter to form more stable sulphur compounds. Sulphur incorporation is likely to be a continuing process throughout diagenesis and catagenesis.

ChemInform Abstract: Synthesis, Isolation, and Full Characterization of the Parent Thiophene 1,1‐Dioxide.

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Synthesis, Isolation, and Full Characterization of the Parent Thiophene 1,1-Dioxide

Synthesis, Isolation, and Full Characterization of the Parent Thiophene 1,1-Dioxide

Structure of Metallathiacycles: Planar vs Nonplanar Geometries. A Theoretical and Experimental Investigation

Since the previously reported results of Fenske−Hall molecular orbital calculations suggested that the bent metallacycle geometries observed in transition-metal-inserted thiophene complexes do not result from electronic properties, molecular mechanics calculations were employed to explore how steric factors could influence ring geometries. These calculations have identified steric factors responsible for the observed ring deformations in (C5Me5)Rh(PMe3)(η2-C,S-2,5-Me2C4H2S) and benzothiophene and dibenzothiophene analogs. The results of the molecular mechanics calculations have been supported by X-ray structural characterization of the products formed via insertion of the reactive 16-electron metal fragment [(C5Me5)Rh(PMe3)] into the C−S bonds of unsubstituted thiophene, benzothiophene, and dibenzothiophene. The parent thiophene complex, unlike the previously reported ring-substituted analog (and as predicted by the molecular mechanics calculations) is found to adopt a planar six-membered ring structure. ...

In situ spectroscopic study of the electropolymerization and properties of polyterthiophene

The electrochemical polymerization of terthiophene has been studied using time resolvedin situ UV-visible transmission spectroscopy. The similarity of monomer and polymer oxidation potentials allows one to deposit partially or fully doped polymer. Both coulometric and spectroscopic data show that the level of doping increases with polymerization potential up to about 1.1 V, at which point it attains its maximum value of one positive charge per four rings, as for the parent thiophene. At the relatively low polymerization potentials employed, incompletely polymerized material is trapped within the polymer film. Direct evidence for the presence of trapped monomer is the disappearance of a peak at 355 nm upon the application of positive potentials to a film transferred to monomer-free background electrolyte. Spectroscopic and coulometric assay of these species shows that they constitute an appreciable fraction (ca. 20%) of the immobilized material at low polymerization potentials. The ability of these species to remain unpolymerized decreases with increasing polymerization potential. In all cases, they are polymerized during subsequent potential cycling in the range 0.0–1.15V. The redox composition of the polymer, estimated using optical data, shows non-Nernstian behaviour.

Geometric and electronic structures of isothianaphthene and thieno[3,4-C]thiophene: A theoretical investigation

We present a theoretical (MNDO-SCF-MO and VEH) investigation of the geometry and electronic properties of isothianaphthene (benzo[c]-thiophene) and another thiophene derivative, thieno[3,4-c]thiophene. Our goal is to understand better, at the molecular level, the reasons for a small band-gap in polyisothianaphthene and possibly to guide the organic synthesis towards other interesting polymeric materials. Compared to the parent thiophene molecule, isothianaphthene and thieno[3,4-c]thiophene possess significantly lower ionization potentials and present a strongly conjugated path along their periphery.