Correspondence on "Organo-Mediator Enabled Electrochemical Deuteration of Styrenes".

The recently reported electrochemical, organo-mediator enabled deuteration of styrenes, a reaction referred to as "electrochemical deuterium atom transfer", differs mechanistically from reported direct electrochemical hydrogenations/deuterations only by a mediated, homogeneous SET to the substrates. By comparing direct vs. mediated processes in general and for styrene reduction, we display that Qiu's work does not change the concept of this chemistry. Experiments with mediators and the direct reduction of examples from the reported scope show that even electron-rich substrates can be reduced when our direct protocol, published six months before Qiu's work, is applied.

Linear Amine-Linked Oligo-BODIPYs: Convergent Access via Buchwald-Hartwig Coupling.

A convergent route toward nitrogen-bridged BODIPY oligomers has been developed. The synthetic key step is a Buchwald-Hartwig cross-coupling reaction of an α-amino-BODIPY and the respective halide. Not only does the selective synthesis provide control of the oligomer size, but the facile preparative procedure also enables easy access to these types of dyes. Furthermore, functionalized examples were accessible via brominated derivatives.

Water-Soluble Fluorescent Polymer Dyes with Tunable Emission Spectra for Flow Cytometry Applications.

The application of spectrally unique, bright, and water-soluble fluorescent dyes is indispensable for the analysis of biological systems. Multiparameter flow cytometry is a powerful tool for characterization of mixed cell populations. To discriminate the different cell populations, they are typically stained by a set of fluorescent reagents, e.g., antibody-fluorophore conjugates. The number of parameters which can be studied simultaneously strongly depends on the availability of reagents which can be differentiated by their spectral properties. In this study a series of fluorescent polymer dyes was developed, that can be excited with a single violet laser (405 nm) but distinguished by their unique emission spectra. The polyfluorene-based polymers can be used on their own, or in combination with covalently bound small-molecule dyes to generate energy transfer constructs to red-shift the emission wavelength based on Förster resonance energy transfer (FRET). The polymer dyes were utilized in a biological flow cytometry assay by conjugating several of them to antibodies, demonstrating their effectiveness as reagents. This report represents the first systematic investigation of structure-property relationships for this type of fluorescent dyes.

Copper-Assisted (Pseudo-)Halochalcogenation of Arynes.

In this report, we describe the multicomponent coupling reaction between arynes, (pseudo)halides, and an electrophilic chalcogen species. Addition of a copper salt enabled smooth conversion by suppressing side reactions. A variety of different aryne precursors as well as seleno- and thiosulfonates were employed, yielding a broad spectrum of ortho-(pseudo)halogenated chalcogenides. This motif was subjected to different cross-coupling approaches, demonstrating the applicability of these compounds as building blocks for more complex structures.

Electrochemical Diselenation of BODIPY Fluorophores for Bioimaging Applications and Sensitization of 1 O2.

Invited for the cover of this issue are the groups of Holger Braunschweig at the Julius-Maximilians-Universität Würzburg, Germany and Eufrânio N. da Silva Júnior at the Universidade Federal de Minas Gerais, UFMG, Brazil. The image depicts the electrochemical synthesis of selenium-containing BODIPY molecules with lightning symbolizing the electrifying synthetic process, while the surrounding elemental chaos hints at the red-shifted absorption and emission and the transformative photophysical properties of these new compounds. Read the full text of the article at 10.1002/chem.202303883.

Electrochemical Diselenation of BODIPY Fluorophores for Bioimaging Applications and Sensitization of 1 O2.

We report a rapid, efficient, and scope-extensive approach for the late-stage electrochemical diselenation of BODIPYs. Photophysical analyses reveal red-shifted absorption - corroborated by TD-DFT and DLPNO-STEOM-CCSD computations - and color-tunable emission with large Stokes shifts in the selenium-containing derivatives compared to their precursors. In addition, due to the presence of the heavy Se atoms, competitive ISC generates triplet states which sensitize 1 O2 and display phosphorescence in PMMA films at RT and in a frozen glass matrix at 77 K. Importantly, the selenium-containing BODIPYs demonstrate the ability to selectively stain lipid droplets, exhibiting distinct fluorescence in both green and red channels. This work highlights the potential of electrochemistry as an efficient method for synthesizing unique emission-tunable fluorophores with broad-ranging applications in bioimaging and related fields.

Highly scalable photoinduced synthesis of silanols via untraversed pathway for chlorine radical (Cl•) generation.

The emergence of visible light-mediated synthetic transformations has transpired as a promising approach to redefine traditional organic synthesis in a sustainable way. In this genre, transition metal-mediated photoredox catalysis has led the way and recreated a plethora of organic transformations. However, the use of photochemical energy solely to initiate the reaction is underexplored. With the direct utilization of photochemical energy herein, we have established a general and practical protocol for the synthesis of diversely functionalized organosilanols, silanediols, and polymeric siloxanol engaging a wide spectrum of hydrosilanes under ambient reaction conditions. Streamlined synthesis of bio-active silanols via late-stage functionalization underscores the importance of this sustainable protocol. Interestingly, this work also reveals photoinduced non-classical chlorine radical (Cl•) generation from a readily available chlorinated solvent under aerobic conditions. The intriguing factors of the proposed mechanism involving chlorine and silyl radicals as intermediates were supported by a series of mechanistic investigations.

Access to isoindole-derived BODIPYs by an aminopalladation cascade.

Here, we present a new route to dyes of the BODIPY family. We first built up a N-Boc-protected dipyrromethene scaffold via an aminopalladation cascade. Subsequentially, the pyrrole moiety was deprotected and the BF2 unit inserted. Depending on the terminating reaction, BODIPYs with either aryl or alkynyl moieties were accessible.

Fluorophore position of headgroup-labeled Gb3 glycosphingolipids in lipid bilayers.

Fluorescent lipid probes are an invaluable tool for investigating lipid membranes. In particular, localizing certain receptor lipids such as glycosphingolipids within phase-separated membranes is of pivotal interest to understanding the influence of protein-receptor lipid binding on membrane organization. However, fluorescent labeling can readily alter the phase behavior of a lipid membrane because of the interaction of the fluorescent moiety with the membrane interface. Here, we investigated Gb3 glycosphingolipids, serving as receptor lipids for the protein Shiga toxin, with a headgroup attached BODIPY fluorophore separated by a polyethylene glycol (PEG) spacer of different lengths. We found that the diffusion coefficients of the fluorescently labeled Gb3 species in 1,2-dioleoyl-sn-glycero-3-phosphocholine/Gb3 (98:2, n/n) supported lipid bilayers are unaltered by the PEG spacer length. However, quenching as well as graphene-induced energy transfer experiments indicated that the length of the PEG spacer (n = 3 and n = 13) alters the position of the BODIPY fluorophore. In particular, the graphene-induced energy transfer technique provided accurate end-to-end distances between the fluorophores in the two leaflets of the bilayer thus enabling us to quantify the distance between the membrane interface and the fluorophore with sub-nanometer resolution. The spacer with three oligo ethylene glycol groups positioned the BODIPY fluorophore directly at the membrane interface favoring its interaction with the bilayer and thus may disturb lipid packing. However, the longer PEG spacer (n = 13) separated the BODIPY moiety from the membrane surface by 1.5 nm.

Ring-Opening 1,3-Sulfonylation-Fluorination of Donor-Acceptor Cyclopropanes: Three-Component Access to γ-Fluorosulfones.

A general method for 1,3-bisfunctionalization of donor-acceptor (D-A) cyclopropanes using sulfinate salts and electrophilic fluorination reagents is described. Utilizing Lewis acid catalysis, nucleophilic ring-opening by the sulfinate anion followed by trapping of electrophilic fluorine by the anionic intermediate leads to the formation of γ-fluorosulfones. To the best of our knowledge, this is the first direct one-step synthesis of sulfones fluorinated in the γ-position from a carbon backbone. A mechanistic proposal is presented based on experimental evidence.

Site-selective Hydrogenation/Deuteration of Benzylic Olefins Enabled by Electroreduction Using Water.

We describe an operationally simple and user-friendly protocol that allows the site-selective hydrogenation and deuteration of di-, tri- and tetrasubstituted benzylic olefins by electroreduction while other groups prone to hydrogenation are present. The radical anionic intermediates react with the most inexpensive hydrogen/deuterium source H2 O/D2 O. Our method overcomes many limitations that arise from previously reported electroreductive hydrogenations. The applicability of this reaction is demonstrated by a broad substrate scope (>50 examples) that focuses on functional group tolerance and sites that are affected by metal-catalyzed hydrogenation (alkenes, alkynes, protecting groups).

Optical Manipulation of Gb3 Enriched Lipid Domains: Impact of Isomerization on Gb3 -Shiga Toxin B Interaction.

The plasma membrane is a complex assembly of proteins and lipids that can self-assemble in submicroscopic domains commonly termed "lipid rafts", which are implicated in membrane signaling and trafficking. Recently, photo-sensitive lipids were introduced to study membrane domain organization, and photo-isomerization was shown to trigger the mixing and de-mixing of liquid-ordered (lo ) domains in artificial phase-separated membranes. Here, we synthesized globotriaosylceramide (Gb3 ) glycosphingolipids that harbor an azobenzene moiety at different positions of the fatty acid to investigate light-induced membrane domain reorganization, and that serve as specific receptors for the protein Shiga toxin (STx). Using phase-separated supported lipid bilayers on mica surfaces doped with four different photo-Gb3 molecules, we found by fluorescence microscopy and atomic force microscopy that liquid disordered (ld ) domains were formed within lo domains upon trans-cis photo-isomerization. The fraction and size of these ld domains were largest for Gb3 molecules with the azobenzene group at the end of the fatty acid. We further investigated the impact of domain reorganization on the interaction of the B-subunits of STx with the photo-Gb3 . Fluorescence and atomic force micrographs clearly demonstrated that STxB binds to the lo phase if Gb3 is in the trans-configuration, whereas two STxB populations are formed if the photo-Gb3 is switched to the cis-configuration highlighting the idea of manipulating lipid-protein interactions with a light stimulus.

Donor-Acceptor Cyclopropanes: Activation Enabled by a Single, Vinylogous Acceptor.

A novel class of highly activated donor-acceptor cyclopropanes bearing only a single, vinylogous acceptor is presented. These strained moieties readily undergo cycloadditions with aldehydes, ketones, thioketones, nitriles, naphth-2-ols and various other substrates to yield the corresponding carbo- and heterocycles. Diastereocontrol can be achieved through the choice of catalyst (Brønsted or Lewis acid). The formation of tetrahydrofurans was shown to be highly enantiospecific when chiral cyclopropanes are employed. A series of mechanistic and kinetic experiments was conducted to elucidate a plausible catalytic cycle and to rationalize the stereochemical outcome.

A Widely Applicable and Versatile Method for the Ring-Opening 1,3-Carbocarbonation of Donor-Acceptor Cyclopropanes.

A 1,3-carbocarbonation of 2-substituted cyclopropane 1,1-dicarboxylates introduces various saturated or unsaturated carbon residues at the 1- and 3- position of the former three-membered ring. Under copper catalysis, ring-opening attack with a Grignard reagent proceeded smoothly; the intermediate was converted to the final product by reaction with appropriate carbon-based electrophiles under basic conditions. As nucleophiles, Grignard reagents derived from sp3 -, sp2 -, and sp-hybridized carbon residues were successfully employed, whereas various aliphatic bromides and EBX derivatives (for sp moieties) served as electrophiles.

Non-directed Pd-catalysed electrooxidative olefination of arenes.

The Fujiwara-Moritani reaction is a powerful tool for the olefination of arenes by Pd-catalysed C-H activation. However, the need for superstoichiometric amounts of toxic chemical oxidants makes the reaction unattractive from an environmental and atom-economical view. Herein, we report the first non-directed and regioselective olefination of simple arenes via an electrooxidative Fujiwara-Moritani reaction. The versatility of this operator-friendly approach was demonstrated by a broad substrate scope which includes arenes, heteroarenes and a variety of olefins. Electroanalytical studies suggest the involvement of a Pd(ii)/Pd(iv) catalytic cycle via a Pd(iii) intermediate.

The Interaction of Gb3 Glycosphingolipids with ld and lo Phase Lipids in Lipid Monolayers Is a Function of Their Fatty Acids.

The glycosphingolipid Gb3 is a specific receptor of the bacterial Shiga toxin (STx). Binding of STx to Gb3 is a prerequisite for its internalization into the host cells, and the ceramide's fatty acid of Gb3 has been shown to influence STx binding. In in vitro studies on liquid ordered (lo)/liquid disordered (ld) coexisting artificial membranes, Shiga toxin B (STxB) binds solely to lo domains, thus harboring Gb3 concomitant with an observed lipid redistribution process. These findings raise the question of how the molecular structure of the fatty acid of Gb3 influences the interaction of Gb3 with the different lipids preferentially either found in the lo phase, namely, sphingomyelin and cholesterol, or in the ld phase. We addressed this question by using a series of synthetically available and unlabeled Gb3 glycosphingolipids carrying different long chain C24 fatty acids (saturated, monounsaturated, and α-hydroxylated). In conjunction with surface tension experiments on Langmuir monolayers, we quantified the excess of free energy of mixing of the different Gb3 species in monolayers composed of either sphingomyelin or cholesterol or composed of a fluid phase lipid (DOPC). From a calculation of the total free energy of mixing, we conclude that mixing of the saturated Gb3 species with the ld lipid DOPC is energetically less favorable than all other combinations, while the unsaturated species mix equally well with the lo phase lipids sphingomyelin and cholesterol and the ld phase lipid DOPC. Furthermore, we found that STxB partially penetrates in mixed lipid monolayers (DOPC/sphingomyelin/cholesterol) containing the Gb3 sphingolipid with a saturated or a monounsaturated C24 fatty acid. The maximum insertion pressure, as a measure for protein insertion, is >30 mN/m for both Gb3 molecules and is not significantly different for the two Gb3 species.

Insertion of S2 into Donor-Acceptor Cyclopropanes: Access to Dithiolanes and Their Conversion to Thietane Dioxides.

A facile and efficient route to dithiolanes starting from donor-acceptor cyclopropanes is reported. Potassium p-toluenethiosulfonate has been established as the reagent of choice for this formal insertion of the disulfide moiety. Using this methodology, dithiolanes have been synthesized in moderate to good yields with high functional group tolerance. Upon treatment with an excess of mCPBA, the corresponding dithiolanes delivered four-membered thietane dioxides, the formal (3+1)-cycloaddition product of D-A cyclopropanes, and sulfur dioxide.

Pd-catalysed C-H functionalisation of free carboxylic acids.

Pd-catalysed C-H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to the predominance of carboxylic acid moieties in pharmaceuticals and agrochemicals. But their coordinating ability was overlooked and masked by exogenous directing groups for a long time. Even other crucial roles of carboxylic acids as additives and steric inducers that directly influence the mode of a reaction have been widely neglected. This review aims to embrace all of the diverse aspects of carboxylic acids except additive and steric effects by concisely and systematically describing their versatile role in Pd-catalysed proximal and distal C-H activation reactions that could be implemented in the pharmaceutical and agrochemical industries. In addition, the mechanistic perspectives along with several recent strategies developed in the last few years discussed here will serve as educational resources for future research.

C-H deuteration of organic compounds and potential drug candidates.

C-H deuteration has been intricately developed to satisfy the urgent need for site-selectively deuterated organic frameworks. Deuteration has been primarily used to study kinetic isotope effects of reactions but recently its significance in pharmaceutical chemistry has been discovered. Deuterium labelled compounds have stolen the limelight since the inception of the first FDA-approved deuterated drug, for the treatment of chorea-associated Huntington's disease, and their pharmacological importance was realised by chemists, although surprisingly very late. Various approaches were developed to carry out site-selective deuteration. However, the most common and efficient method is hydrogen isotope exchange (HIE). This review summarises deuteration methods of various organic motifs containing C(sp2)-H and C(sp3)-H bonds utilizing C-H bond functionalisation as a key step along with a variety of catalysts, and exemplifies their biological relevance.

Transforming Dyes into Fluorophores: Exciton-Induced Emission with Chain-like Oligo-BODIPY Superstructures.

Herein we present a systematic study demonstrating to which extent exciton formation can amplify fluorescence based on a series of ethylene-bridged oligo-BODIPYs. A set of non- and weakly fluorescent BODIPY motifs was selected and transformed into discrete, chain-like oligomers by linkage via a flexible ethylene tether. The prepared superstructures constitute excitonically active entities with non-conjugated, Coulomb-coupled oscillators. The non-radiative deactivation channels of Internal Conversion (IC), also combined with an upstream reductive Photoelectron Transfer (rPET) and Intersystem Crossing (ISC) were addressed at the monomeric state and the evolution of fluorescence and (non-)radiative decay rates studied along the oligomeric series. We demonstrate that a "masked" fluorescence can be fully reactivated irrespective of the imposed conformational rigidity. This work challenges the paradigm that a collective fluorescence enhancement is limited to sterically induced motional restrictions.