Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach.

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly solvents, such as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) belonging to classes 3 and 2, respectively. Beyond decreasing the environmental impact of the synthesis (E-factor: 24.1-54.9 with VOCs; 12.2-22.1 with 2-MeTHF or CPME), this switch also improved the overall yield of the process (from 10% with VOCs to 21-22% with 2-MeTHF or CPME) and remarkably simplified the manual operations, working under milder conditions. Typical metrics applied at the first and second pass, according to the CHEM21 metrics toolkit, were also calculated for the whole synthetic procedure of dimethindene, and the results were compared with those of the classical procedure.

"Inherently Chiral" Ionic-Liquid Media: Effective Chiral Electroanalysis on Achiral Electrodes.

To achieve enantioselective electroanalysis either chiral electrodes or chiral media are needed. High enantiodiscrimination properties can be granted by the "inherent chirality" strategy of developing molecular materials in which the stereogenic element responsible for chirality coincides with the molecular portion responsible for their specific properties, an approach recently yielding outstanding performances as electrode surfaces. Inherently chiral ionic liquids (ICILs) have now been prepared starting from atropisomeric 3,3'-bicollidine, synthesized from inexpensive reagents, resolved into antipodes without need of chiral HPLC and converted into long-chain dialkyl salts with melting points below room temperature. Both the new ICILs and shorter family terms, solid at room temperature, employed as low-concentration additives in achiral ILs, afford impressive enantioselection for the enantiomers of different probes on achiral electrodes, regularly increasing with additive concentration.

Inherently Chiral Spider-Like Oligothiophenes.

The racemate of an inherently chiral "spider-like" octathiophene monomer T83 , in which chirality is generated by torsion in its backbone, was synthesized. The racemate was resolved into configurationally stable antipodes by HPLC on a chiral stationary phase. Electrooxidation of the enantiomers resulted in materials displaying high enantiorecognition ability towards the antipodes of some chiral probes. Moreover, the T83 racemate demonstrated great aptitude to stimulate formation of 3D rigid architectures if used as a cross-linking monomer for molecular imprinting. This feature was exploited to devise a molecularly imprinted polymer-based chemosensor selective for a thymine-adenine oligonucleotide.

"Inherently chiral" thiophene-based electrodes at work: a screening of enantioselection ability toward a series of pharmaceutically relevant phenolic or catecholic amino acids, amino esters, and amine.

"Inherently chiral" thiophene-based electroactive oligomer films have recently been shown to exhibit outstanding chirality manifestations. One of the most exciting among them is an unprecedented enantioselection ability as electrode surfaces. In fact, in preliminary chiral voltammetry experiments, the new electrodes have been shown to both discriminate the enantiomers of chiral probes (either enantiopure or in a mixture, in terms of large differences in peak potentials) and quantify them (in terms of linear dynamic ranges in peak currents), without the need for preliminary separation steps. Such ability has now been tested on a series of chiral DOPA-related molecules, from phenolic amino acid tyrosine (together with its methyl ester) to catecholic amino acid DOPA (together with its methyl ester), to catecholamine epinephrine (adrenaline). The wide-range enantioselectivity of the new inherently chiral electrode surfaces is fully confirmed, as large peak potential differences are obtained for probe enantiomers of the whole series working in common aqueous buffers. Moreover, interesting modulating effects on enantiodiscrimination can be observed as a function of both molecular structure and pH. Graphical abstract Inherently chiral thiophene-based electrodes at work with pharmaceutically relevant probes.

Determination of the Enantiomerization Barrier of the Residual Enantiomers of C3 -Symmetric Tris[3-(1-Methyl-2-Alkyl)Indolyl]Phosphane Oxides: Case Study of a Multitasking HPLC Investigation Based on an Immobilized Polysaccharide Stationary Phase.

The residual enantiomers of three tris-(3-indolyl)-phosphane oxides bearing different alkyl groups (methyl, ethyl or i-propyl) in position 2 of the indole rings constituting the blades were separated on the immobilized type Chiralpak IC column in polar organic and reversed-phase modes. The good enantioselectivity and versatility of the IC CSP allowed easy isolation of the enantiomerically highly enriched samples suitable for configurational stability studies. The enantiomerization barriers of residual phosphane oxides were evaluated both by off-column techniques (CD signal and enantiomeric purity decay kinetics) and by dynamic enantioselective high-performance liquid chromatography (HPLC).

Inherently chiral macrocyclic oligothiophenes: easily accessible electrosensitive cavities with outstanding enantioselection performances.

Linear conjugated oligothiophenes of variable length and different substitution pattern are ubiquitous in technologically advanced optoelectronic devices, though limitations in application derive from insolubility, scarce processability and chain-end effects. This study describes an easy access to chiral cyclic oligothiophenes constituted by 12 and 18 fully conjugated thiophene units. Chemical oxidation of an "inherently chiral" sexithiophene monomer, synthesized in two steps from commercially available materials, induces the formation of an elliptical dimer and a triangular trimer endowed with electrosensitive cavities of different tunable sizes. Combination of chirality with electroactivity makes these molecules unique in the current oligothiophenes literature. These macrocycles, which are stable and soluble in most organic solvents, show outstanding chiroptical properties, high circularly polarized luminescence effects and an exceptional enantiorecognition ability.

Dinuclear rhenium complexes as redox-active pendants in a novel electrodeposited polycyclopentadithiophene material.

The novel [Re2(µ-H)(µ-OOC-CPDT)(CO)6(µ-3-Me-pydz)] complex (1; OOC-CPDT = 4H-cyclopenta[2,1-b:3,4-b']dithiophene-4-carboxylate, 3-Me-pydz = 3-methylpyridazine) has been prepared and characterized by single-crystal X-ray diffraction, density functional theory (DFT), and time-dependent DFT computations, UV-vis absorption and emission spectroscopy, and cyclic voltammetry (CV). The measured properties indicate the lack of electronic communication in the ground state between the CPDT and the rhenium diazine moieties. Oxidative electropolymerization of 1, achieved by repeated potential cycling (-0.4 to +1.0 V vs Fc(+)/Fc, in acetonitrile) with different supporting electrolytes, on different electrodes, afforded an electroactive and stable metallopolymer (poly-1). In situ measurements of the mass of the growing film (on a gold electrode, with an electrochemical quartz microbalance) confirmed the regularity of the polymerization process. The polymer exhibits two reversible oxidation peaks of the thiophene chain and a broad irreversible reduction peak (-1.4 V, quite close to that observed for the reduction of monomer 1), associated with a remarkably delayed sharp return peak, of comparable associated charge, appearing in close proximity (+0.3 V) to the first oxidation peak of the neutral polythiophene chain. This charge-trapping effect can be observed upon repeated cycles of p and n doping, and the negative charge is maintained even if the charged electrode is removed from the solution for many hours. Electrochemical impedance spectroscopy showed that the main CV oxidation peak corresponds to facile charge transfer, combined with very fast diffusion of both electrons and ions within the polymer. In summary, poly-1 provides a new example of a metallopolymer, in which the conductive properties of the π-conjugated system are added to the redox behavior of the pendant-isolated complexes.

Potential-driven chirality manifestations and impressive enantioselectivity by inherently chiral electroactive organic films.

The typical design of chiral electroactive materials involves attaching chiral pendants to an electroactive polyconjugated backbone and generally results in modest chirality manifestations. Discussed herein are electroactive chiral poly-heterocycles, where chirality is not external to the electroactive backbone but inherent to it, and results from a torsion generated by the periodic presence of atropisomeric, conjugatively active biheteroaromatic scaffolds, (3,3'-bithianaphthene). As the stereogenic element coincides with the electroactive one, films of impressive chiroptical activity and outstanding enantiodiscrimination properties are obtained. Moreover, chirality manifestations can be finely and reversibly tuned by the electric potential, as progressive injection of holes forces the two thianaphthene rings to co-planarize to favor delocalization. Such deformations, revealed by CD spectroelectrochemistry, are elastic and reversible, thus suggesting a breathing system.

Steric and electronic effects on the configurational stability of residual chiral phosphorus-centered three-bladed propellers: tris-aryl phosphane oxides.

A series of tris-aryl phosphane oxides existing as residual enantiomers or diastereoisomers with substituents on the aryl rings differing in size and electronic properties were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation and reduction potentials together with those of the corresponding "blade bromides" (i.e., the naphthalene derivatives displaying the same substitution pattern of the tris-naphthyl phosphane oxide blades, with a bromo substituent where the phosphorus atom is located) determined by CV. The residual stereoisomeric phosphane oxides were isolated in a stereochemically pure state and were found to be highly configurationally stable at room temperature (stereoisomerization barriers of about 27 kcal mol(-1)). The chiroptical properties of the residual stereoisomers and the assignments of absolute configuration are discussed. The configurational stability of residual tris-aryl phosphane oxides was found to be scarcely influenced by the electronic properties of the substituents present on the aromatic rings constituting the blades, while steric effects play the most relevant role. Detailed theoretical calculations are in agreement with the experimental results and also contribute to a rational interpretation of the stereodynamics of these systems.

Steric and electronic effects on the configurational stability of residual chiral phosphorus-centered three-bladed propellers: tris-aryl phosphanes.

A series of tris-aryl phosphanes, structurally designed to exist as residual enantiomers or diastereoisomers, bearing substituents differing in size and electronic properties on the aryl rings, were synthesized and characterized. Their electronic properties were evaluated on the basis of their electrochemical oxidation potential determined by voltammetry. The configurational stability of residual phosphanes, evaluated by dynamic HPLC on a chiral stationary phase or/and by dynamic (1)H and (31)P NMR spectroscopy, was found to be rather modest (barriers of about 18-20 kcal mol(-1)), much lower than that shown by the corresponding phosphane oxides (barriers of about 25-29 kcal mol(-1)). For the first time, the residual antipodes of a tris-aryl phosphane were isolated in enantiopure state and the absolute configuration assigned to them by single-crystal anomalous X-ray diffraction analysis. In this case, the racemization barrier could be calculated also by CD signal decay kinetics. A detailed computational investigation was carried out to clarify the helix reversal mechanism. Calculations indicated that the low configurational stability of tris-aryl phosphanes can be attributed to an unexpectedly easy phosphorus pyramidal inversion which, depending upon the substituents present on the blades, can occur even on the most stable of the four conformers constituting a single residual stereoisomer.

Towards molecular design rationalization in branched multi-thiophene semiconductors: the 2-thienyl-persubstituted alpha-oligothiophenes.

The introduction of branching in multi-thiophene semiconductors, although granting the required solubility for processing, results in an increased molecular fluxionality and a higher level of distortion, thus hampering pi conjugation. Accordingly, branched oligothiophenes require rationalization of their structure-reactivity relationships for target-oriented design and optimization of the synthetic effort. Our current research on spiderlike oligothiophenes affords deep insight into the subject, and introduces new, easily accessible molecules with attractive functional properties. In particular, a regular series, T'X(Y), of five new multi-thiophene systems, T'5(3), T'8(4), T'11(5), T'14(6), and T'17(7), constituted by five, eight, 11, 14, and 17 thiophene units, respectively, their longest alpha-conjugated chain consisting of tri-, tetra-, penta-, hexa-, and heptathiophene moieties, respectively, has been synthesized and fully characterized from the structural, spectroscopic, and electrochemical point of view. The electronic properties of the monomers and their electropolymerization ability are discussed and rationalized as a function of their molecular structure, particularly in comparison with the series of 5-(2,2'-dithiophene)yl-persubstituted alpha-oligothiophenes (TX(Y)) previously reported by us. These oligothiophenes are easily accessible materials, with promising properties for applications as active layers in multifunctional organic devices including solar cells.

Melamine acoustic chemosensor based on molecularly imprinted polymer film.

A melamine piezomicrogravimetric (acoustic) chemosensor using a molecularly imprinted polymer (MIP) film has been devised and tested. The MIP films were prepared by electropolymerization of the melamine complexed by the functional monomer of the bis(bithiophene) derivative bearing an 18-crown-6 substituent 4. The structure of the MIP-melamine complex was visualized by the DFT B3LYP/3-21G(*) energy optimization calculations. The sensitivity and selectivity of the MIP film was improved by cross-linking the polymer with the bithianaphthene monomer 5 and the presence of the porogenic ionic liquid in the prepolymerization solution. After electropolymerization, the melamine template was extracted from the MIP film with an aqueous strong base solution. The measurements of UV-vis spectroscopy, X-ray photoelectron spectroscopy (XPS), DPV, and EIS as well as scanning electrochemical microscopy (SECM) imaging confirmed extraction of the melamine template from the MIP film and then rebinding of the melamine analyte while the film relative roughness and porosity was determined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) imaging, respectively. The analytical as well as kinetic and thermodynamic parameters of the chemosensing were assessed under flow-injection analysis (FIA) conditions with piezoelectric microgravimetry (PM) detection. The linear concentration range for melamine detection was 5 nM to at least 1 mM with a limit of detection of approximately 5 nM. The chemosensor successfully discriminated the cyanuric acid, cyromazine, and ammeline interfering agents.

Chirality in the absence of rigid stereogenic elements: the design of configurationally stable C3-symmetric propellers.

Residual stereoisomerism is a form of stereoisomerism scarcely considered so far for applicative purposes, though extremely interesting, since the production of stereoisomers does not involve classical rigid stereogenic elements. In three-bladed propeller-shaped molecules, a preferred stereomerization mechanism, related to the correlated rotation of the rings, allows the free interconversion of stereoisomers inside separated sets (the residual stereoisomers) that can interconvert through higher energy pathways. In light of possible future applications as chiral ligands for transition metals in stereoselective processes, some C(3)-symmetric phosphorus-centered propellers, which could exist as residual enantiomers, are synthesized and the possibility of resolving their racemates into residual antipodes is explored. While the tris(aryl)methanes are configurationally stable at room temperature, only selected tris(aryl)phosphane oxides display a configurational stability high enough to allow resolution by HPLC on a chiral stationary phase (CSP HPLC) at a semipreparative level at room temperature. Stability was evaluated through different techniques (circular dichroism (CD) signal decay, dynamic CSP HPLC (CSP DHPLC), dynamic NMR analysis (DNMR)) and the results compared and discussed. Phosphanes were found much less stable than the corresponding phosphane oxides, for which preliminary calculations suggest that the three-ring-flip enantiomerization mechanism (M(0)) would be easier than phosphorus pyramidal inversion. The parameters affecting the configurational stability of the residual enantiomers of C(3)-symmetric propellers are discussed.

Chirality in the absence of rigid stereogenic elements: the absolute configuration of residual enantiomers of C3-symmetric propellers.

Two new tris(aryl)phosphane oxides existing as configurationally stable residual enantiomers have been synthesised and their racemates resolved by semipreparative HPLC on a chiral stationary phase (CSP HPLC). One of them, recognised as a conglomerate, could be resolved by fractional crystallisation at a preparative scale level. In this case, the absolute configuration of the propeller-shaped molecule was determined by anomalous X-ray scattering. The problem of the correlative assignment of the absolute configuration to all known C(3)-symmetric three-bladed propeller-shaped molecules existing as stable residual enantiomers is discussed. The configurational stability of the new chiral phosphane oxides and of the corresponding phosphanes was evaluated by CD signal decay kinetics and dynamic (1)H NMR spectroscopy. The racemisation barriers in phosphanes were found about 10 kcal mol(-1) lower than those found for the corresponding oxides, though geometry and inter-ring gearing would be very similar in the two series. Configurational stability of residual tris(aryl)phosphanes was found to be influenced by the electronic availability of the phosphorus centre, as evaluated by electrochemical CV experiments.

Programmed Transfer of Sequence Information into a Molecularly Imprinted Polymer for Hexakis(2,2'-bithien-5-yl) DNA Analogue Formation toward Single-Nucleotide-Polymorphism Detection.

A new strategy of simple, inexpensive, rapid, and label-free single-nucleotide-polymorphism (SNP) detection using robust chemosensors with piezomicrogravimetric, surface plasmon resonance, or capacitive impedimetry (CI) signal transduction is reported. Using these chemosensors, selective detection of a genetically relevant oligonucleotide under FIA conditions within 2 min is accomplished. An invulnerable-to-nonspecific interaction molecularly imprinted polymer (MIP) with electrochemically synthesized probes of hexameric 2,2'-bithien-5-yl DNA analogues discriminating single purine-nucleobase mismatch at room temperature was used. With density functional theory modeling, the synthetic procedures developed, and isothermal titration calorimetry quantification, adenine (A)- or thymine (T)-substituted 2,2'-bithien-5-yl functional monomers capable of Watson-Crick nucleobase pairing with the TATAAA oligodeoxyribonucleotide template or its peptide nucleic acid (PNA) analogue were designed. Characterized by spectroscopic techniques, molecular cavities exposed the ordered nucleobases on the 2,2'-bithien-5-yl polymeric backbone of the TTTATA hexamer probe designed to hybridize the complementary TATAAA template. In that way, an artificial TATAAA-promoter sequence was formed in the MIP. The purine nucleobases of this sequence are known to be recognized by RNA polymerase to initiate the transcription in eukaryotes. The hexamer strongly hybridized TATAAA with the complex stability constant KsTTTATA-TATAAA = ka/kd ≈ 106 M-1, as high as that characteristic for longer-chain DNA-PNA hybrids. The CI chemosensor revealed a 5 nM limit of detection, quite appreciable as for the hexadeoxyribonucleotide. Molecular imprinting increased the chemosensor sensitivity to the TATAAA analyte by over 4 times compared to that of the nonimprinted polymer. The herein-devised detection platform enabled the generation of a library of hexamer probes for typing the majority of SNP probes as well as studying a molecular mechanism of the complex transcription machinery, physics of single polymer molecules, and stable genetic nanomaterials.

Inherently chiral electrodes: the tool for chiral voltammetry.

2,2'-Bis[2-(5,2'-bithienyl)]-3,3'-bithianaphthene oligomers are a model case of electroactive films endowed with "inherent chirality", originating from a stereogenic element coinciding with the whole electroactive backbone, thus resulting in impressive manifestations. This study highlights their applicative potentialities as low-cost and easy-to-prepare artificial enantiopure electrode surfaces, which display an unprecedented ability to pronouncedly separate voltammetry peaks of enantiomers of quite different chiral probes of applicative interest, concurrently with linear dynamic ranges for peak currents, affording enantiomer excess determination. Thus inherently chiral enantiopure electrodes can indeed be regarded as a key to chiral voltammetry.

Cytosine derivatized bis(2,2'-bithienyl)methane molecularly imprinted polymer for selective recognition of 6-thioguanine, an antitumor drug.

A molecularly imprinted polymer (MIP) was designed and synthesized to serve as a functional material for selective recognition of 6-thioguanine (6TG), an antitumor drug. For that, the newly synthesized functional monomer, cytosine-bis(2,2'-bithienyl)-(4-carboxyphenyl)methane ester (Cyt-S4), revealed Watson-Crick type nucleobase pairing of 6TG. Formation of the Cyt-S4 and 6TG complex of the 2:1 stoichiometry was postulated based on the DFT calculations at the B3LYP/3-21G((⁎)) level and experimentally confirmed by fluorescence titration. The molecularly imprinted polymer (MIP) film was deposited by potentiodynamic electropolymerization on a Pt disk electrode as well as on an Au-coated glass slide and on an Au-quartz crystal resonator. The statistical model of formation of this film was successfully simulated by molecular dynamics. Completeness of the subsequent 6TG template extraction from MIP was confirmed by the UV-visible spectroscopy. An imprinting factor of 2.9 for the MIP film was determined by piezoelectric microgravimetry using ECQM. The double-layer capacity and alternating current measurements under flow-injection analysis (FIA) conditions were selected to transduce the 6TG recognition signal into the change of the double-layer capacity dependence on the 6TG concentration in solution for different supporting electrolyte concentrations. Detectability of the resulting chemosensor was 10 µM 6TG for the 0.5 M KF carrier solution in FIA. Selectivity of the chemosensor with respect to common interferences was high, e.g., it exceeded 130 to 2-amino-6-methylmercaptopurine, a 6TG metabolite.

Novel ruthenium(II) complexes with substituted 1,10-phenanthroline or 4,5-diazafluorene linked to a fullerene as highly active second order NLO chromophores.

Various Ru(II) complexes with substituted 1,10-phenanthroline or 4,5-diazafluorene are characterized by a good to very large second order NLO response, as determined by EFISH. Among these complexes, [Ru(9-fulleriden-4,5-diazafluorene)(PPh(3))(2)Cl(2)] is particularly appealing due to its huge second-order NLO response and its transparency to the second harmonic generation. The structure of cis-Cl,trans-PPh(3)-[Ru(5-NO(2)-1,10-phen)(PPh(3))(2)Cl(2))] was determined by single-crystal X-ray diffraction.