Synthesis of 1,6/7-(NO2 )2 -Perylenediimide and 1,6/7-(NH2 )2 -Perylenediimide as Regioisomerically Pure Materials.

The use of perylenediimide (PDI) building blocks in materials for organic electronic is of considerable interest. This popular n-type organic semiconductor is tuned by introducing peripheral groups in their ortho and bay positions. Such modifications radically alter their optoelectronic properties. In this article, we describe an efficient method to afford regioisomerically pure 1,6/7-(NO2 )2 - and (NH2 )2 -PDIs employing two key steps: the selective crystallization of 1,6-(NO2 )2 -perylene-3,4,9,10-tetracarboxy tetrabutylester and the nitration of regiopure 1,7-Br2 -PDI with silver nitrite. The optoelectronic properties of the resulting regioisomerically pure dinitro, diamino-PDIs and bisazacoronenediimides (BACDs) are reported and demonstrate the need to separate both regioisomers of such n-type organic semiconductors for their inclusion in advanced optoelectronic devices. For the first time, the two regioisomers of the same PDI starting material are available on the multigram scale, which will stimulate the exploration of regioisomerism/properties relationship for this family of dyes.

An investigation of palladium-catalyzed Stille-type cross-coupling of nitroarenes in perylenediimide series.

We report herein an unprecedented palladium-catalyzed cross-coupling reaction between mononitro-perylenediimide (PDI) and various arylstannanes. Optimized conditions developed with this Stille-type reaction allow the grafting of (hetero)aryls of various electronic nature in the bay region of PDIs. Moreover, we capitalized on the high selectivity of this cross-coupling through the desymmetrization of the dinitro-PDI substrate.

Flipper Probes for the Community.

This article describes four fluorescent membrane tension probes that have been designed, synthesized, evaluated, commercialized and applied to current biology challenges in the context of the NCCR Chemical Biology. Their names are Flipper-TR®, ER Flipper-TR®, Lyso Flipper-TR®, and Mito Flipper-TR®. They are available from Spirochrome.

Mitochondrial membrane tension governs fission.

During mitochondrial fission, key molecular and cellular factors assemble on the outer mitochondrial membrane, where they coordinate to generate constriction. Constriction sites can eventually divide or reverse upon disassembly of the machinery. However, a role for membrane tension in mitochondrial fission, although speculated, has remained undefined. We capture the dynamics of constricting mitochondria in mammalian cells using live-cell structured illumination microscopy (SIM). By analyzing the diameters of tubules that emerge from mitochondria and implementing a fluorescence lifetime-based mitochondrial membrane tension sensor, we discover that mitochondria are indeed under tension. Under perturbations that reduce mitochondrial tension, constrictions initiate at the same rate, but are less likely to divide. We propose a model based on our estimates of mitochondrial membrane tension and bending energy in living cells which accounts for the observed probability distribution for mitochondrial constrictions to divide.

Synthesis and self-assembly of a penta[60]fullerene bearing benzo[ghi]perylenetriimide units.

A benzo[ghi]perylenetriimide (BPTI) derivative bearing a terminal azido group on the expanded π-conjugated backbone has been synthesized and characterized. This promising photo- and electroactive BPTI motif has been used to obtain an original penta(organo)fullerene as a promising multi-electron acceptor system. Our studies show its self-assembly resulting from aggregation via π-π stacking interaction in solution and in the solid state.

Visible-Light-Mediated Synthesis of AzaBenzannulated Perylenediimide-Based Light-Harvesting Dyads.

Intramolecular imine photocyclization has been explored for grafting on the bay region of perylenediimide (PDI) different electro- and photoactive chromophores to achieve new AzaBenzannulated-PDI (AzaBPDI) dyads. Triphenylamine (TPA), fluorene (Fl), perylenemonoimide (PMI), and perylenediimide (PDI) units have been successfully assembled to AzaBPDI using this straightforward one-pot synthesis starting from the easily accessible 1-aminoPDI. This original procedure was compared to the well-known Pictet-Spengler reaction and appears to be an attractive alternative in terms of versatility and efficiency with higher yields obtained. The optical and electrochemical properties of these molecular systems demonstrated large absorption capabilities in the visible range, good accepting abilities with low LUMO levels, and efficient electronic interactions between chromophoric units such as energy or electron transfers. In addition, with their large dihedral angle estimated by theoretical calculations, those dyads should present interesting applications in various organic optoelectronic devices. In particular, the PMI-AzaBPDI and PDI-AzaBPDI dyads presenting low LUMO levels, a broad absorption in the visible range, and a twisted conformation make them good candidates as non-fullerene acceptors in organic solar cells.

Endosomal membrane tension regulates ESCRT-III-dependent intra-lumenal vesicle formation.

The plasma membrane tension strongly affects cell surface processes, such as migration, endocytosis and signalling. However, it is not known whether the membrane tension of organelles regulates their functions, notably intracellular traffic. The endosomal sorting complexes required for transport (ESCRT)-III complex is the major membrane remodelling complex that drives intra-lumenal-vesicle (ILV) formation on endosomal membranes. Here we used a fluorescent membrane-tension probe to show that ESCRT-III subunits are recruited onto endosomal membranes when the membrane tension is reduced. We find that tension-dependent recruitment is associated with ESCRT-III polymerization and membrane deformation in vitro and correlates with increased ILV formation in ESCRT-III-decorated endosomes in vivo. Finally, we find that the endosomal membrane tension decreases when ILV formation is triggered by EGF under physiological conditions. These results indicate that membrane tension is a major regulator of ILV formation and endosome trafficking, leading us to conclude that membrane tension can control organelle functions.

Desymmetrization of Perylenediimide Bay Regions Using Selective Suzuki-Miyaura Reactions from Dinitro Substituted Derivatives.

Bay decoration of perylenediimide (PDI) is an attractive approach for tuning the optoelectronic properties of the dye as well as breaking backbone planarity, which provides the possibility of preventing the undesired formation of aggregates. This is usually performed through successive bis-bromination of PDI and pallado-catalyzed cross-coupling, which leads to symmetric triads. We now describe an efficient synthetic strategy for desymmetrization of the accepting PDI core by starting from its bis-nitration. To this end, Suzuki-Miyaura Couplings (SMC) were carried out on a mixture of 1,6- and 1,7-dinitroPDI regioisomers to add triphenylamine donating moieties and obtain donor-acceptor-donor triads. Investigation of the reactivity of dinitro PDI derivatives toward SMC has allowed us to access unprecedented asymmetric π-conjugated PDI-centered triads. These 1,6- and 1,7-PDI based triads, prepared as regioisomeric mixtures, were successfully separated and their spectroscopic, crystallographic and optoelectronic differences are reported.

An Imine Photocyclization as an Alternative to the Pictet-Spengler Reaction for the Synthesis of AzaBenzannulated Perylenediimide Dyes.

AzaBenzannulated perylenediimide (AzaBPDI) dyes were synthesized in high yields via a new reaction sequence involving an imine condensation followed by visible light-induced photocyclization. The large scope and efficiency of this alternative to the Pictet-Spengler reaction are demonstrated, allowing easy preparation of dimeric AzaBPDI as potential non-fullerene acceptors for organic solar cells.

Nitro-Perylenediimide: An Emerging Building Block for the Synthesis of Functional Organic Materials.

Perylenediimide (PDI) is one of the most important classes of dyes and is intensively explored in the field of functional organic materials. The functionalization of this electron-deficient aromatic core is well-known to tune the outstanding optoelectronic properties of PDI derivatives. In this respect, the functionalization has been mostly addressed in bay-positions to halogenated derivatives through nucleophilic substitutions or metal-catalyzed coupling reactions. Being aware of the synthetic difficulties of obtaining the key intermediate 1-bromoPDI, we will present as an alternative in this review the potential of 1-nitroPDI: a powerful building block to access a large variety of PDI-based materials.

Palmitate and oleate modify membrane fluidity and kinase activities of INS-1E ß-cells alongside altered metabolism-secretion coupling.

Chronic exposure to elevated levels of glucose and free fatty acids impairs beta-cell function, leading to insulin secretion defects and eventually beta-cell failure. Using a semi-high throughput approach applied to INS-1E beta-cells, we tested multiple conditions of chronic exposure to basal, intermediate and high glucose, combined with saturated versus mono- and polyunsaturated fatty acids in order to assess cell integrity, lipid metabolism, mitochondrial function, glucose-stimulated calcium rise and secretory kinetics. INS-1E beta-cells were cultured for 3 days at different glucose concentrations (5.5, 11.1, 25 mM) without or with BSA-complexed 0.4 mM saturated (C16:0 palmitate), monounsaturated (C18:1 oleate) or polyunsaturated (C18:2 linoleate, C18:3 linolenate) fatty acids, resulting in 0.1-0.5 µM unbound fatty acids. Accumulation of triglycerides in cells exposed to fatty acids was glucose-dependent, oleate inducing the strongest lipid storage and protecting against glucose-induced cytotoxicity. The combined chronic exposure to both high glucose and either palmitate or oleate altered mitochondrial function as well as glucose-induced calcium rise. This pattern did not directly translate at the secretory level since palmitate and oleate exhibited distinct effects on the first and the second phases of glucose-stimulated exocytosis. Both fatty acids changed the activity of kinases, such as the MODY-associated BLK. Additionally, chronic exposure to fatty acids modified membrane physicochemical properties by increasing membrane fluidity, oleate exhibiting larger effects compared to palmitate. Chronic fatty acids differentially and specifically exacerbated some of the glucotoxic effects, without promoting cytotoxicity on their own. Each of the tested fatty acids functionally modified INS-1E beta-cell, oleate inducing the strongest effects.

A Chalcogen-Bonding Cascade Switch for Planarizable Push-Pull Probes.

Planarizable push-pull probes have been introduced to demonstrate physical forces in biology. However, the donors and acceptors needed to polarize mechanically planarized probes are incompatible with their twisted resting state. The objective of this study was to overcome this "flipper dilemma" with chalcogen-bonding cascade switches that turn on donors and acceptors only in response to mechanical planarization of the probe. This concept is explored by molecular dynamics simulations as well as chemical double-mutant cycle analysis. Cascade switched flipper probes turn out to excel with chemical stability, red shifts adding up to high significance, and focused mechanosensitivity. Most important, however, is the introduction of a new, general and fundamental concept that operates with non-trivial supramolecular chemistry, solves an important practical problem and opens a wide chemical space.

Dithienothiophenes at Work: Access to Mechanosensitive Fluorescent Probes, Chalcogen-Bonding Catalysis, and Beyond.

In this review, the multifunctionality of dithieno[3,2-b:2',3'-d]thiophenes (DTTs) is covered comprehensively. This is of interest because all involved research is very recent and emphasizes timely topics such as mechanochemistry for bioimaging or chalcogen bonds for catalysis and solar cells and because the newly emerging privileged scaffold is embedded in an inspiring structural space. At the beginning, DTTs are introduced with regard to nomenclature, constitutional isomers, and optoelectronic properties. The structural space around DTTs is mapped out next with regard to heteroatom substitution in the bridge and core, covering much of the periodic table, eccentric heteroatom doping, and bridge expansions. After a brief summary of synthetic approaches to the DTT scaffold, chalcogen bonds are introduced as, together with redox switching and turn-on fluorescence, one of the three conceptual foundations of the most multifunctionality. Realized functions cover anion binding, transport (ion carriers, ion channels), catalysis, and the first fluorescent probes to image physical forces in living cells. The appearance of DTTs in many other photosystems covers push-pull systems for nonlinear optics and dye-sensitized solar cells, DTT polymers in light-emitting diodes, organic field-effect transistors and organic photovoltaics, DTT self-assembly and templated assembly into thin films and fluorescent fibers, also within cells, and the integration of DTTs into photochromes and biaromatics that violate the Hückel rule..

Mechanosensitive Fluorescent Probes to Image Membrane Tension in Mitochondria, Endoplasmic Reticulum, and Lysosomes.

Measuring forces inside cells is particularly challenging. With the development of quantitative microscopy, fluorophores which allow the measurement of forces became highly desirable. We have previously introduced a mechanosensitive flipper probe, which responds to the change of plasma membrane tension by changing its fluorescence lifetime and thus allows tension imaging by FLIM. Herein, we describe the design, synthesis, and evaluation of flipper probes that selectively label intracellular organelles, i.e., lysosomes, mitochondria, and the endoplasmic reticulum. The probes respond uniformly to osmotic shocks applied extracellularly, thus confirming sensitivity toward changes in membrane tension. At rest, different lifetimes found for different organelles relate to known differences in membrane organization rather than membrane tension and allow colabeling in the same cells. At the organelle scale, lifetime heterogeneity provides unprecedented insights on ER tubules and sheets, and nuclear membranes. Examples on endosomal trafficking or increase of tension at mitochondrial constriction sites outline the potential of intracellularly targeted fluorescent tension probes to address essential questions that were previously beyond reach.

Streptavidin interfacing as a general strategy to localize fluorescent membrane tension probes in cells.

To image the mechanical properties of biological membranes, twisted push-pull mechanophores that respond to membrane tension by planarization in the ground state have been introduced recently. For their application in biological systems, these so-called fluorescent flippers will have to be localized to specific environments of cellular membranes. In this report, we explore streptavidin as a versatile connector between biotinylated flipper probes and biotinylated targets. Fluorescence spectroscopy and microscopy with LUVs and GUVs reveal the specific conditions needed for desthiobiotin-loaded streptavidin to deliver biotinylated flippers selectively to biotinylated membranes. Selectivity for biotinylated plasma membranes is also observed in HeLa cells, confirming the compatibility of this strategy with biological systems. Streptavidin interfacing does not affect the mechanosensitivity of the flipper probes, red shift in the excitation maximum and fluorescence lifetime increase with membrane order and tension, as demonstrated, inter alia, using FLIM.

Integration of molecular machines into supramolecular materials: actuation between equilibrium polymers and crystal-like gels.

In this article, the dynamic structure of complex supramolecular polymers composed of bistable [c2]daisy chain rotaxanes as molecular machines that are linked by ureidopyrimidinones (Upy) as recognition moieties was studied. pH actuation of the integrated mechanically active rotaxanes controls the contraction/extension of the polymer chains as well as their physical reticulation. Small-angle neutron and X-ray scattering were used to study in-depth the nanostructure of the contracted and extended polymer aggregates in toluene solution. The supramolecular polymers comprising contracted nanomachines were found to be equilibrium polymers with a mass that is concentration dependent in dilute and semidilute regimes. Surprisingly, the extended polymers form a gel network with a crystal-like internal structure that is independent of concentration and reminiscent of a pearl-necklace network.

Bistable [c2] Daisy Chain Rotaxanes as Reversible Muscle-like Actuators in Mechanically Active Gels.

The implementation of molecular machines in polymer science is of high interest to transfer mechanical motions from nanoscale to macroscale in order to access new kinds of active devices and materials. Toward this objective, thermodynamic and topological aspects need to be explored for reaching efficient systems capable of producing a useful work. In this paper we describe the branched polymerization of pH-sensitive bistable [c2] daisy chain rotaxanes by using copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition ("click chemistry"). With this cross-linked topology, the corresponding materials in the form of chemical gels can be contracted and expanded over a large variation of volume (∼50%) by changing the protonation state of the system. HR-MAS 1H NMR and neutron scattering experiments reveal that this macroscopic response of the gels results from the synchronized actuation of the mechanical bonds at the molecular level.

Dual-light control of nanomachines that integrate motor and modulator subunits.

A current challenge in the field of artificial molecular machines is the synthesis and implementation of systems that can produce useful work when fuelled with a constant source of external energy. The first experimental achievements of this kind consisted of machines with continuous unidirectional rotations and translations that make use of 'Brownian ratchets' to bias random motions. An intrinsic limitation of such designs is that an inversion of directionality requires heavy chemical modifications in the structure of the actuating motor part. Here we show that by connecting subunits made of both unidirectional light-driven rotary motors and modulators, which respectively braid and unbraid polymer chains in crosslinked networks, it becomes possible to reverse their integrated motion at all scales. The photostationary state of the system can be tuned by modulation of frequencies using two irradiation wavelengths. Under this out-of-equilibrium condition, the global work output (measured as the contraction or expansion of the material) is controlled by the net flux of clockwise and anticlockwise rotations between the motors and the modulators.

Controlled Sol-Gel Transitions by Actuating Molecular Machine Based Supramolecular Polymers.

The implementation of artificial molecular machines in polymer science is an important objective that challenges chemists and physicists in order to access an entirely new class of smart materials. To design such systems, the amplification of a mechanical actuation from the nanoscale up to a macroscopic response in the bulk material is a central issue. In this article we show that bistable [c2]daisy chain rotaxanes (i.e., molecular muscles) can be linked into main-chain Upy-based supramolecular polymers. We then reveal by an in depth quantitative study that the pH actuation of the mechanically active rotaxane at the nanoscale influences the physical reticulation of the polymer chains by changing the supramolecular behavior of the Upy units. This nanoactuation within the local structure of the main chain polymer results in a mechanically controlled sol-gel transition at the macroscopic level.