Wireless Hollow Miniaturized Objects for Electroassisted Chiral Resolution.

Chiral resolution plays a crucial role in the field of drug development, especially for a better understanding of biochemical processes. In such a context, classic separation methods have been used for decades due to their versatility and easy scale-up. Among the many attempts proposed for enantioselective separation, electroassisted methods are presented as an interesting alternative. Herein, we present the use of wirelessly activated hollow tubular systems for the effective, simple, and tunable separation of racemic and enantioenriched mixtures. These double-layered tubular objects consist of an external polypyrrole chassis, a polymer with good electromechanical properties, functionalized in its inner part with an inherently chiral oligomer. The synergy between the electromechanical pumping process of the outer layer and the enantioselective affinity of the inner part induces the system to behave as a miniaturized chiral column. These hybrid objects are able to separate racemic and enantioenriched solutions of chiral model analytes into the corresponding enantiomers in high enantiomeric purity. Finally, these electromechanical systems can resolve mixtures formed by chiral probes with completely uncorrelated molecular structures injected simultaneously into the single antipodes.

Designing Powerful Biindole-Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements.

Among inherently chiral selectors of axial stereogenicity, usually resulting in very good enantiodiscrimination performances, the biindole-based family has the additional advantage of very easy functionalization of the two nitrogen atoms with a variety of substituents with desirable properties. Aiming to evaluate the possibility of exploiting such feature to enhance the enantiodiscrimination ability of the archetype structure, a series of three inherently chiral monomers were designed and synthesized, characterised by a 2,2'-biindole atropisomeric core conjugated to bithiophene wings enabling fast and regular electrooligomerization, and functionalised at the nitrogen atoms with an ethyl, a methoxyethyl, or a hydroxyethyl substituent. Nitrogen alkylation was also exploited to obtain for the first time the chemical resolution of the biindole selectors without employing chiral HPLC. The enantiodiscrimination ability of the selector series was comparatively evaluated in proof-of-concept chiral voltammetry experiments with a "benchmark" chiral ferrocenyl probe as well as with chiral non-steroidal anti-inflammatory drugs naproxen and ketoprofen. The large enantiomer potential differences for all probes increased in the ethyl < methoxyethyl ≪ hydroxyethyl sequence of selector substituents, supporting our assumption on the beneficial role of an additional coordination element. The powerful hydroxyethyl selector was also applied to ketoprofen in a commercial drug matrix.

Green Synthesis of a Molecularly Imprinted Polymer Based on a Novel Thiophene-Derivative for Electrochemical Sensing.

An environmentally friendly and sustainable approach was adopted to produce a molecularly imprinted polymer (MIP) via electropolymerization, with remarkable electrochemical sensing properties, tested in tyrosine (tyr) detection. The 2,2'-bis(2,2'-bithiophene-5-yl)-3,3'-bithianaphtene (BT2-T4) was chosen as functional monomer and MIP electrosynthesis was carried out via cyclic voltammetry on low-volume (20 µL) screen-printed carbon electrodes (C-SPE) in ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ((BMIM) TFSI). An easy and rapid washing treatment allowed us to obtain the resulting MIP film, directly used for tyr electrochemical detection, carried out amperometrically. The sensor showed a linear response in the concentration range of 15-200 µM, with LOD of 1.04 µM, LOQ of 3.17 µM and good performance in selectivity, stability, and reproducibility. Tyrosine amperometric detection was also carried out in human plasma, resulting in a satisfactory recovery estimation. The work represents the first use of BT2-T4 as a functional monomer for the production of a molecularly imprinted polymer, with a green approach afforded by using a few microliters of a room temperature ionic liquid as an alternative to common organic solvents on screen-printed carbon electrodes, resulting in a valuable system that meets the green chemistry guidelines, which is today an essential criterion in both research and application field.

Magnetic field-enhanced redox chemistry on-the-fly for enantioselective synthesis.

Chemistry on-the-fly is an interesting concept, extensively studied in recent years due to its potential use for recognition, quantification and conversion of chemical species in solution. In this context, chemistry on-the-fly for asymmetric synthesis is a promising field of investigation, since it can help to overcome mass transport limitations, present for example in conventional organic electrosynthesis. Herein, the synergy between a magnetic field-enhanced self-electrophoretic propulsion mechanism and enantioselective redox chemistry on-the-fly is proposed as an efficient method to boost stereoselective conversion. We employ Janus swimmers as redox-active elements, exhibiting a well-controlled clockwise or anticlockwise motion with a speed that can be increased by one order of magnitude in the presence of an external magnetic field. While moving, these bifunctional objects convert spontaneously on-the-fly a prochiral molecule into a specific enantiomer with high enantiomeric excess. The magnetic field-enhanced self-mixing of the swimmers, based on the formation of local magnetohydrodynamic vortices, leads to a significant improvement of the reaction yield and the conversion rate.

Wireless electromechanical enantio-responsive valves.

Microfluidic valves based on chemically responsive materials have gained considerable attention in recent years. Herein, a wireless enantio-responsive valve triggered by bipolar electrochemistry combined with chiral recognition is reported. A conducting polymer actuator functionalized with the enantiomers of an inherently chiral oligomer was used as bipolar valve to cover a tube loaded with a dye and immersed in a solution containing chiral analytes. When an electric field is applied, the designed actuator shows a reversible cantilever-type deflection, allowing the release of the dye from the reservoir. The tube can be opened and closed by simply switching the polarity of the system. Qualitative results show the successful release of the colorant, driven by chirality and redox reactions occurring at the bipolar valve. The device works well even in the presence of chemically different chiral analytes in the same solution. These systems open up new possibilities in the field of microfluidics, including also controlled drug delivery applications.

HPLC Enantioseparation of Rigid Chiral Probes with Central, Axial, Helical, and Planar Stereogenicity on an Amylose (3,5-Dimethylphenylcarbamate) Chiral Stationary Phase.

The chiral resolving ability of the commercially available amylose (3,5-dimethylphenylcarbamate)-based chiral stationary phase (CSP) toward four chiral probes representative of four kinds of stereogenicity (central, axial, helical, and planar) was investigated. Besides chirality, the evident structural feature of selectands is an extremely limited conformational freedom. The chiral rigid analytes were analyzed by using pure short alcohols as mobile phases at different column temperatures. The enantioselectivity was found to be suitable for all compounds investigated. This evidence confirms that the use of the amylose-based CSP in HPLC is an effective strategy for obtaining the resolution of chiral compounds containing any kind of stereogenic element. In addition, the experimental retention and enantioselectivity behavior, as well as the established enantiomer elution order of the investigated chiral analytes, may be used as key information to track essential details on the enantiorecognition mechanism of the amylose-based chiral stationary phase.

Autonomous Chiral Microswimmers with Self-mixing Capabilities for Highly Efficient Enantioselective Synthesis.

The development of chiral catalysts plays a very important role in various areas of chemical science. Heterogeneous catalysts have the general advantage of allowing a more straightforward separation from the products. One specific case of heterogeneous catalysis is electrocatalysis, being potentially a green chemistry approach. However, a typical drawback is that the redox conversion of molecules occurs only at the electrode/electrolyte interface, and not in the bulk of the electrolyte. The second limitation is that the electrodes have to be physically connected to a power supply to induce the desired reactions. To circumvent these problems, we propose here a complementary approach by replacing macroscopic electrodes with an ensemble of self-propelled redox active microswimmers. They move autonomously in solution while transforming simultaneously a prochiral starting compound into a specific enantiomer with a very high enantiomeric excess, accompanied by a significantly increased production rate of the favorite enantiomer.

Modulating the Enantiodiscrimination Features of Inherently Chiral Selectors by Molecular Design: A HPLC and Voltammetry Study Case with Atropisomeric 2,2'-Biindole-Based Monomers and Oligomer Films.

A family of inherently chiral electroactive selectors based on the 2,2'-biindole atropisomeric scaffold, of easy synthesis and modulable functional properties, is studied in cascade in two enantioselection contexts. They are at first investigated as probes in enantioselective HPLC, studying molecular structure and temperature effects, and achieving very efficient semipreparative enantioseparation. The enantiomers thus obtained, of remarkable chiroptical features (optical rotation as well as circular dichroism), are successfully applied as selectors in chiral voltammetry in different media for discrimination of the enantiomers of chiral electroactive probes, either by conversion into enantiopure electroactive electrode surfaces by electrooligomerization on glassy carbon substrate (the two monomers with shorter alkyl chains), or as chiral additive in achiral ionic liquid (the monomer with longest alkyl chains). Discrimination is conveniently and reproducibly achieved in terms of significant potential differences for the two enantiomers, specularly inverting either probe or selector configuration. In one case successful discrimination is also observed with the two probe enantiomers concurrently present, either as racemate or with enantiomeric excesses, neatly accounted for by the peak current ratios.

Hybrid light-emitting devices for the straightforward readout of chiral information.

Bipolar electrochemistry has gained increasing attention in recent years as an attractive transduction concept in analytical chemistry in general and, more specifically, in the frame of chiral recognition. Herein, we use this concept of wireless electrochemistry, based on the combination of the enantioselective oxidation of a chiral probe with the emission of light from a light-emitting diode (LED), as an alternative for an easy and straightforward readout of the presence of chiral molecules in solution. A hybrid polymer-microelectronic device was designed, using an inherently chiral oligomer, that is, oligo-(3,3'-dibenzothiophene) and a polypyrrole strip as the anode and cathode of a miniaturized LED. The wireless induced redox reactions trigger light emission when the probe with the right chirality is present in solution, whereas no light emission is observed for the opposite enantiomer. The average light intensity shows a linear correlation with the analyte concentration, and the concept opens the possibility to quantify the enantiomeric excess in mixtures of the molecular antipodes.

Multimilligram-scale production implementation of atropisomers of 2,2'-bis(2,2'-bithiophene-5-yl)-3,3'-bithianaphthene.

2,2'-Bis[2-(5,2'-bithienyl)]-3,3'-bithianaphthene (1) is the progenitor of a class of C2 symmetric thiophene-based electroactive monomers that, when electrooxidized in the enantiomerically pure form, produce inherently chiral films endowed with outstanding electrochemical enantiorecognition properties. The enantioselective high-performance liquid chromatography (HPLC) is the only approach used so far to resolve the racemic form of 1 into enantiomers. In this work, an improved HPLC method for multimilligram enantiomer production is presented. Key factors controlling the enantioseparation, such as mobile phase composition and column temperature, were identified using a 100 × 4.6 mm i.d. Chiralpak IB-3 column and subsequently scaled up to a 250 × 10.0 mm i.d. Chiralpak IB column. In the optimized semipreparative conditions, about 34 mg of pure (P) and (M) enantiomers per hour could be produced.

Absolute Chiral Recognition with Hybrid Wireless Electrochemical Actuators.

Chiral discrimination is of crucial importance for many applications, including drug cross checking and electronic tongue-type devices. In a typical sensing scheme, an enantiomeric selector is combined with an appropriate transduction mechanism. We propose here a hybrid material composed of an electrically conducting oligomer i.e. oligo-(3,3'-dibenzothiophene) bearing inherently chiral features and polypyrrole as a support, which can undergo electrochemical actuation. The combination of both leads to a freestanding film that is addressable in a wireless way based on the principle of bipolar electrochemistry. The induced redox reactions lead to well-pronounced actuation when DOPA with the right chirality is present in solution as a model analyte, whereas absolutely no electromechanical response is measured for the wrong enantiomer. This constitutes a straightforward and absolute read out of chiral information where the amplitude of actuation is correlated with the concentration of the analyte. Optimization of the scheme results in highly efficient bending and thus opens up new directions in the field of chiral technologies.

Characterization of Inherently Chiral Electrosynthesized Oligomeric Films by Voltammetry and Scanning Electrochemical Microscopy (SECM).

A voltammetric and scanning electrochemical microscopy (SECM) investigation was performed on an inherently chiral oligomer-coated gold electrode to establish its general properties (i.e., conductivity and topography), as well as its ability to discriminate chiral electroactive probe molecules. The electroactive monomer (S)-2,2'-bis(2,2'-bithiophene-5-yl)-3,3'-bibenzothiophene ((S)-BT2T4) was employed as reagent to electrodeposit, by cyclic voltammetry, the inherently chiral oligomer film of (S)-BT2T4 (oligo-(S)-BT2T4) onto the Au electrode surface (resulting in oligo-(S)-BT2T4-Au). SECM measurements, performed in either feedback or competition mode, using the redox mediators [Fe(CN)6]4- and [Fe(CN)6]3- in aqueous solutions, and ferrocene (Fc), (S)-FcEA, (R)-FcEA and rac-FcEA (FcEA is N,N-dimethyl-1-ferrocenylethylamine) in CH3CN solutions, indicated that the oligomer film, as produced, was uncharged. The use of [Fe(CN)6]3- allowed establishing that the oligomer film behaved as a porous insulating membrane, presenting a rather rough surface. This was inferred from both the approach curves and linear and bidimensional SECM scans, which displayed negative feedback effects. The oligomer film acquired semiconducting or fully conducting properties when the Au electrode was biased at potential more positive than 0.6 V vs. Ag|AgCl|KCl. Under the latter conditions, the approach curves displayed positive feedback effects. SECM measurements, performed in competition mode, allowed verifying the discriminating ability of the oligo-(S)-BT2T4 film towards the (S)-FcEA and (R)-FcEA redox mediators, which confirmed the results obtained by cyclic voltammetry. SECM linear scans indicated that the enantiomeric discriminating ability of the oligo-(S)-BT2T4 was even across its entire surface.

Effective Enantiodiscrimination in Electroanalysis Based on a New Inherently Chiral 1,1'-binaphthyl Selector Directly Synthesizable in Enantiopure Form.

Enantioselective electroanalysis, which aims to discriminate the enantiomers of electroactive chiral probes in terms of potential difference, is a very attractive goal. To achieve this, its implementation is being studied for various "inherently chiral" selectors, either at the electrode surface or in the medium, yielding outstanding performance. In this context, the new inherently chiral monomer Naph2T4 is introduced, based on a biaromatic atropisomeric core, which is advantageously obtainable in enantiopure form without HPLC separation steps by a synthetic route hinging on enantiopure 2,2'-dibromo-1,1'-binaphthalenes. The antipodes of the new inherently chiral monomer can be easily electrooligomerized, yielding inherently chiral electrode surfaces that perform well in both cyclic voltammetry (CV) enantiodiscrimination tests with pharmaceutically interesting molecules and in magnetoelectrochemistry experiments.

Metal-Free Alpha Trifluoromethylselenolation of Carbonyl Derivatives under Batch and Flow Conditions.

Trifluoromethylselenolated carbonyl compounds represent an emerging class with potential applications in several fields; however, a widespread use of such compound is hampered by the very limited number of strategies for their preparation. In this study we developed a method for the preparation of α-SeCF3 substituted carbonyl derivatives using an in situ generated electrophilic ClSeCF3 species. We also implemented an in-flow protocol to improve the safety features of the process.

Searching for Models Exhibiting High Circularly Polarized Luminescence: Electroactive Inherently Chiral Oligothiophenes.

Two new inherently chiral oligothiophenes characterized by the atropisomeric 3,3'-bithianaphtene scaffold functionalized with fused ring bithiophene derivatives, namely 4H-cyclopenta[2,1-b3:4b']dithiophene (CPDT) and dithieno[3,3-b:2',3'-d]pyrrole (DTP), were synthesized. The racemates were fully characterized and resolved into antipodes by enantioselective HPLC. The enantiomers were analyzed through different chiroptical techniques: electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) were employed to attribute the absolute configuration (AC). Comparison of experimental and calculated VCD spectra confirmed the DFT calculated conformational characteristics. The compound functionalized with two CPDT units was oxidized with FeCl3 , and ECD and CPL of the resulting material were measured. Circularly polarized luminescence (CPL) was measured to verify if inherently chiral oligothiophenes could be promising systems for chiral photonics applications.

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.

Discrimination of Axial and Central Stereogenic Elements in Chiral Bis(oxazolines) Based on Atropisomeric 3,3'-Bithiophene Scaffolds Through Chiroptical Spectroscopies.

Two diastereoisomeric pairs of bis-oxazolines, provided with a stereogenic center at carbon 4 and based on the 3,3'-bithiophene atropisomeric scaffold, were synthesized and structurally characterized. They differ in the substituents at positions 2 and 5 of the thiophene rings, which are functionalized with methyl (1) or phenyl (2) groups, respectively. In vibrational circular dichroism (VCD) spectra, recorded in CCl4 solutions, it is possible to distinctly recognize the characteristic features of axial and central stereogenic elements. In tandem with Density Functional Theory (DFT) calculations, the absolute configuration (AC) of the diastereoisomers was safely established. In this case, VCD was shown to be superior to ECD (electronic circular dichroism) in the assignment of AC. The normal modes, evaluated from DFT calculations, show that the VCD signals in correspondence with the stereogenic axis of the bithiophene unit are different for 1 and 2. The VCD spectra of a molecular analog of 1, the (S)-2,2',5,5'-tetramethyl-4,4'-bis-(diphenylphosphino)-3,3'-bithiophene oxide (3), characterized by the same 3,3'-bithiophene scaffold, but devoid of stereogenic centers, exhibits signals similar to those observed in the case of diastereoisomer (aS,R,R)-1a, associated with almost identical normal modes. Chirality 28:686-695, 2016. © 2016 Wiley Periodicals, Inc.

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.