Easy and accurate computation of energy barriers for carbocation solvation: an expeditious tool to face carbocation chemistry.

An expeditious procedure for the challenging computation of the free energy barriers (ΔG≠) for the solvation of carbocations is presented. This procedure is based on Marcus Theory (MT) and the popular B3LYP/6-31G(d)//PCM method, and it allows the easy, accurate and inexpensive prediction of these barriers for carbocations of very different stability. This method was validated by the fair mean absolute error (ca. 1.5 kcal mol-1) achieved in the prediction of 19 known experimental barriers covering a range of ca. 50 kcal mol-1. Interestingly, the new procedure also uses an original method for the calculation of the required inner reorganization energy (Λi) and free energy of reaction (ΔG). This procedure should pave the way to face computationally the pivotal issue of carbocation chemistry and could be easily extended to any bimolecular organic reaction.

Formylation as a Chemical Tool to Modulate the Performance of Photosensitizers Based on Boron Dipyrromethene Dimers.

Heavy-atom-free photosensitizers are envisioned as the next generation of photoactive molecules for photo-theragnosis. In this approach, and after suitable irradiation, a single molecular scaffold is able to visualize and kill tumour cells by fluorescence signalling and photodynamic therapy (PDT), respectively, with minimal side effects. In this regard, BODIPY-based orthogonal dimers have irrupted as suitable candidates for this aim. Herein, we analyse the photophysical properties of a set of formyl-functionalized BODIPY dimers to ascertain their suitability as fluorescent photosensitizers. The conducted computationally aided spectroscopic study determined that the fluorescence/singlet oxygen generation dual performance of these valuable BODIPY dimers not only depends on the BODIPY-BODIPY linkage and the steric hindrance around it, but also can be modulated by proper formyl functionalization at specific chromophoric positions. Thus, we propose regioselective formylation as an effective tool to modulate such a delicate photonic balance in BODIPY-based dimeric photosensitizers. The taming of the excited-state dynamics, in particular intramolecular charge transfer as the key underlying process mediating fluorescence deactivation vs. intersystem crossing increasing, could serve to increase fluorescence for brighter bioimaging, enhance the generation of singlet oxygen for killing activity, or balance both for photo-theragnosis.

Triplet-triplet sensitizing within pyrene-based COO-BODIPY: a breaking molecular platform for annihilating photon upconversion.

We envisioned a new approach for achieving triplet-triplet annihilation-assisted photon upconversion based on the rational design of a heavy-atom-free, all-organic and photoactivatable triplet-triplet synergistic multichromophoric molecular assembly. This single molecular architecture is easily built by covalently anchoring triplet-annihilator units (pyrenes) to a triplet-photosensitizer moiety (BODIPY), to improve the effectiveness and probability of the required triplet-triplet energy transfer and the ulterior triplet-triplet annihilation. This unprecedented design takes advantage of the high synthetic accessibility and chemical versatility of the COO-BODIPY scaffold. The laser-induced photophysical characterization, assisted by computational simulations (quantum mechanics calculations at single molecular level and molecular dynamics in a solvent cage), identifies the key factors to finely control the intersystem crossing and reverse intersystem crossing probability, pivotal to improve energy transfer efficiency between the involved triplet states. Likewise, theoretical simulations highlight the relevance of the new photoactivable chromophoric design to promote intra- and inter-molecular triplet-triplet annihilation towards enhanced photon upconversion, yielding noticeable fluorescence from pyrene units even under unfavorable conditions (aerated solutions of low concentration at room temperature). The understanding of the complex dynamics sustained by this single molecular architecture could approach the next generation of chemically accessible and low-cost materials enabling fluorescence by photon upconversion mediated by triplet-triplet annihilation.

A Computational-Experimental Approach to Unravel the Excited State Landscape in Heavy-Atom Free BODIPY-Related Dyes.

We performed a time-gated laser-spectroscopy study in a set of heavy-atom free single BODIPY fluorophores, supported by accurate, excited-state computational simulations of the key low-lying excited states in these chromophores. Despite the strong fluorescence of these emitters, we observed a significant fraction of time-delayed (microseconds scale) emission associated with processes that involved passage through the triplet manifold. The accuracy of the predictions of the energy arrangement and electronic nature of the low-lying singlet and triplet excited states meant that an unambiguous assignment of the main deactivation pathways, including thermally activated delayed fluorescence and/or room temperature phosphorescence, was possible. The observation of triplet state formation indicates a breakthrough in the "classic" interpretation of the photophysical properties of the renowned BODIPY and its derivatives.

From photosensitizers to light harvesters adapting the molecular structure in all-BODIPY assemblies.

Herein we detail a protocol to design dyads and triads based solely on BODIPY dyes as halogen-free singlet oxygen photosensitizers or energy transfer molecular cassettes. The conducted photonic characterization reveals the key role of the BODIPY-BODIPY linkage to finely modulate the balance between the triplet state population and fluorescence decay.

Manipulating Charge-Transfer States in BODIPYs: A Model Strategy to Rapidly Develop Photodynamic Theragnostic Agents.

On the basis of a family of BINOL (1,1'-bi-2-naphthol)-based O-BODIPY (dioxyboron dipyrromethene) dyes, it is demonstrated that chemical manipulation of the chromophoric push-pull character, by playing with the electron-donating capability of the BINOL moiety (BINOL versus 3,3'-dibromoBINOL) and with the electron-acceptor ability of the BODIPY core (alkyl substitution degree), is a workable strategy to finely balance fluorescence (singlet-state emitting action) versus the capability to photogenerate cytotoxic reactive oxygen species (triplet-state photosensitizing action). It is also shown that the promotion of a suitable charge-transfer character in the involved chromophore upon excitation enhances the probability of an intersystem crossing phenomenon, which is required to populate the triple state enabling singlet oxygen production. The reported strategy opens up new perspectives for rapid development of smarter agents for photodynamic theragnosis, including heavy-atom-free agents, from a selected organic fluorophore precursor.

BCl3-Activated Synthesis of COO-BODIPY Laser Dyes: General Scope and High Yields under Mild Conditions.

A general and straightforward method for the synthesis of COO-BODIPYs from F-BODIPYs and carboxylic acids is established. The method is based on the use of boron trichloride to activate the involved substitution of fluorine, which leads to high yields through rapid reactions under soft conditions. This mild method opens the way to unprecedented laser dyes with outstanding efficiencies and photostabilities, which are difficult to obtain by the current methods.

Chiral Microneedles from an Achiral Bis(boron dipyrromethene): Spontaneous Mirror Symmetry Breaking Leading to a Promising Photoluminescent Organic Material.

Supramolecular self-assembly of a highly flexible and achiral meso bis(boron dipyrromethene) [bis(BODIPY)] dye straightforwardly yields fluorescent microfibers, exhibiting an intriguing anisotropic photonic behavior. This performance includes the generation of chiroptical activity owing to spontaneous mirror symmetry breaking (SMSB). Repetition of several self-assembly experiments demonstrates that the involved SMSB is not stochastic but quasi deterministic in the direction of the induced chiral asymmetry. The origin of these intriguing (chiro)photonic properties is revealed by fluorescent microspectroscopy studies of individual micrometric objects, combined with X-ray diffraction elucidation of microcrystals. Such a study demonstrates that J-like excitonic coupling between bis(BODIPY) units plays a fundamental role in their supramolecular organization, leading to axial chirality. Interestingly, the photonic behavior of the obtained fibers is ruled by inherent nonradiative pathways from the involved push-pull chromophores, and mainly by the complex excitonic interactions induced by their anisotropic supramolecular organization.

N-BODIPYs Come into Play: Smart Dyes for Photonic Materials.

N-BODIPYs (diaminoboron dipyrromethenes) are unveiled as a new family of BODIPY dyes with huge technological potential. Synthetic access to these systems has been gained through a judicious design focused on stabilizing the involved diaminoboron chelate. Once stabilized, the obtained N-BODIPYs retain the effective photophysical behavior exhibited by other boron-substituted BODIPYs, such as O-BODIPYs. However, key bonding features of nitrogen compared to those of oxygen (enhanced bond valence and different bond directionality) open up new possibilities for functionalizing BODIPYs, allowing an increase in the number of pendant moieties (from two in O-BODIPYs, up to four in N-BODIPYs) near the chromophore and, therefore, greater control of the photophysics. As a proof of concept, the following findings are discussed: (1) the low-cost and straightforward synthesis of a selected series of N-BODIPYs; (2) their outstanding photophysical properties compared to those of related effective dyes (excellent emission signatures, including fluorescence in the solid state; notable lasing capacities in the liquid phase and when doped into polymers; improved laser performance compared to the parent F-BODIPYs); (3) the versatility of the diaminoboron moiety in allowing the generation of multifunctionalized BODIPYs, permitting access to both symmetric and asymmetric dyes; (4) the capability of such versatility to finely modulate the dye photophysics towards different photonic applications, from lasing to chemosensing.

Rational Design of Advanced Photosensitizers Based on Orthogonal BODIPY Dimers to Finely Modulate Singlet Oxygen Generation.

The synthesis, photophysical characterization, and modeling of a new library of halogen-free photosensitizers (PS) based on orthogonal boron dipyrromethene (BODIPY) dimers are reported. Herein we establish key structural factors in order to enhance singlet oxygen generation by judiciously choosing the substitution patterns according to key electronic effects and synthetic accessibility factors. The photosensitization mechanism of orthogonal BODIPY dimers is demonstrated to be strongly related to their intrinsic intramolecular charge transfer (ICT) character through the spin-orbit charge-transfer intersystem crossing (SOCT-ISC) mechanism. Thus, singlet oxygen generation can be effectively modulated through the solvent polarity and the presence of electron-donating or withdrawing groups in one of the BODIPY units. The photodynamic therapy (PDT) activity is demonstrated by in vitro experiments, showing that selected photosensitizers are efficiently internalized into HeLa cells, exhibiting low dark toxicity and high phototoxicity, even at low PS concentration (0.05-5×10-6 m).

Circularly polarized laser emission in optically active organic dye solutions.

The generation of circularly polarized laser emission (CPLE) in photonic devices has attracted increasing attention due to the prospects of using CP light in displaying technologies or advanced microscopies. Organic systems excel as laser materials across the whole visible spectrum, and despite many of them displaying circularly polarized luminescence (CPL), none have been shown thus far to amplify their own CPL, let alone generate CPLE. Consequently, there is still a need to find alternative CPLE organic devices. Herein we demonstrate an effective strategy for achieving strong levels of CPLE (|glum| ∼ 0.1-0.2) by using solutions of an achiral dye dissolved in optically active solvents to exploit the full potential of the dynamic birefringence induced by the intense and polarized laser pumping. The present approach enables changing the CPLE handedness by changing the handedness of the solvent optical activity, opening new avenues for developing cost-effective and easily processable chiro-photonic materials.

Bis(haloBODIPYs) with Labile Helicity: Valuable Simple Organic Molecules That Enable Circularly Polarized Luminescence.

Simple organic molecules (SOM) based on bis(haloBODIPY) are shown to enable circularly polarized luminescence (CPL), giving rise to a new structural design for technologically valuable CPL-SOMs. The established design comprises together synthetic accessibility, labile helicity, possibility of reversing the handedness of the circularly polarized emission, and reactive functional groups, making it unique and attractive as advantageous platform for the development of smart CPL-SOMs.

Exploring the Application of the Negishi Reaction of HaloBODIPYs: Generality, Regioselectivity, and Synthetic Utility in the Development of BODIPY Laser Dyes.

The generality of the palladium-catalyzed C-C coupling Negishi reaction when applied to haloBODIPYs is demonstrated on the basis of selected starting BODIPYs, including polyhalogenated and/or asymmetrical systems, and organozinc reagents. This reaction is an interesting synthetic tool in BODIPY chemistry, mainly because it allows a valuable regioselective postfunctionalization of BODIPY chromophores with different functional groups. In this way, functional patterns that are difficult to obtain by other procedures (e.g., asymmetrically functionalized BODIPYs involving halogenated positions) can now be made. The regioselectivity is achieved by controlling the reaction conditions and is based on almost-general reactivity preferences, and the nature of the involved halogens and their positions. This ability is exemplified by the preparation of a series of new BODIPY dyes with unprecedented substitution patterns allowing noticeable lasing properties.

Circularly Polarized Luminescence from Simple Organic Molecules.

This article aims to show the identity of "circularly polarized luminescent active simple organic molecules" as a new concept in organic chemistry due to the potential interest of these molecules, as availed by the exponentially growing number of research articles related to them. In particular, it describes and highlights the interest and difficulty in developing chiral simple (small and non-aggregated) organic molecules able to emit left- or right-circularly polarized light efficiently, the efforts realized up to now to reach this challenging objective, and the most significant milestones achieved to date. General guidelines for the preparation of these interesting molecules are also presented.

Circularly polarized luminescence by visible-light absorption in a chiral O-BODIPY dye: unprecedented design of CPL organic molecules from achiral chromophores.

Circularly polarized luminescence (CPL) in simple (small, nonaggregated, nonpolymeric) O-BODIPYs (R)-1 and (S)-1 by irradiation with visible light is first detected as proof of the ability of a new structural design to achieve CPL from inherently achiral monochromophore systems in simple organic molecules. The measured level of CPL (|g(lum)|) in solution falls into the usual range of that obtained from other simple organic molecules (10(-5)-10(-2) range), but the latter having more complex architectures since axially chiral chromophores or multichromophore systems are usually required. The new design is based on chirally perturbing the acting achiral chromophore by orthogonally tethering a single axially chiral 1,1'-binaphtyl moiety to it. The latter does not participate as a chromophore in the light-absorption/emission phenomenon. This simple design opens up new perspectives for the future development of new small-sized CPL organic dyes (e.g., those based on other highly luminescent achiral chromophores and/or chirally perturbing moieties), as well as for the improvement of the CPL properties of the organic molecules spanning their use in photonic applications.

A highly fluorescent and readily accessible all-organic photosensitizer model for advancing image-guided cancer PDT.

The potential of using image-guided photodynamic therapy (ig-PDT) for cancer, especially with highly biocompatible fluorescent agents free of heavy atoms, is well recognized. This is due to key advantages related to minimizing adverse side effects associated with standard cancer chemotherapy. However, this theragnostic approach is strongly limited by the lack of synthetically-accessible and easily-modulable chemical scaffolds, enabling the rapid design and construction of advanced agents for clinical ig-PDT. In fact, there are still very few ig-PDT agents clinically approved. Herein we report a readily accessible, easy-tunable and highly fluorescent all-organic small photosensitizer, as a model design for accelerating the development and translation of advanced ig-PDT agents for cancer. This scaffold is based on BODIPY, which assures high fluorescence, accessibility, and ease of performance adaptation by workable chemistry. The optimal PDT performance of this BODIPY dye, tested in highly resistant pancreatic cancer cells, despite its high fluorescent behavior, maintained even after fixation and cancer cell death, is based on its selective accumulation in mitochondria. This induces apoptosis upon illumination, as evidenced by proteomic studies and flow cytometry. All these characteristics make the reported BODIPY-based fluorescent photosensitizer a valuable model for the rapid development of ig-PDT agents for clinical use.

Collective chiroptical activity through the interplay of excitonic and charge-transfer effects in localized plasmonic fields.

The collective light-matter interaction of chiral supramolecular aggregates or molecular ensembles with confined light fields remains a mystery beyond the current theoretical description. Here, we programmably and accurately build models of chiral plasmonic complexes, aiming to uncover the entangled effects of excitonic correlations, intra- and intermolecular charge transfer, and localized surface plasmon resonances. The intricate interplay of multiple chirality origins has proven to be strongly dependent on the site-specificity of chiral molecules on plasmonic nanoparticle surfaces spanning the nanometer to sub-nanometer scale. This dependence is manifested as a distinct circular dichroism response that varies in spectral asymmetry/splitting, signal intensity, and internal ratio of intensity. The inhomogeneity of the surface-localized plasmonic field is revealed to affect excitonic and charge-transfer mixed intermolecular couplings, which are inherent to chirality generation and amplification. Our findings contribute to the development of hybrid classical-quantum theoretical frameworks and the harnessing of spin-charge transport for emergent applications.

Polar ammoniostyryls easily converting a clickable lipophilic BODIPY in an advanced plasma membrane probe.

A very simple, small and symmetric, but highly bright, photostable and functionalizable molecular probe for plasma membrane (PM) has been developed from an accessible, lipophilic and clickable organic dye based on BODIPY. To this aim, two lateral polar ammoniostyryl groups were easily linked to increase the amphiphilicity of the probe and thus its lipid membrane partitioning. Compared to the BODIPY precursor, the transversal diffusion across lipid bilayers of the ammoniostyryled BODIPY probe was highly reduced, as evidenced by fluorescence confocal microscopy on model membranes built up as giant unilamellar vesicles (GUVs). Moreover, the ammoniostyryl groups endow the new BODIPY probe with the ability to optically work (excitation and emission) in the bioimaging-useful red region, as shown by staining of the plasma membrane of living mouse embryonic fibroblasts (MEFs). Upon incubation, this fluorescent probe rapidly entered the cell through the endosomal pathway. By blocking the endocytic trafficking at 4 °C, the probe was confined within the PM of MEFs. Our experiments show the developed ammoniostyrylated BODIPY as a suitable PM fluorescent probe, and confirm the synthetic approach for advancing PM probes, imaging and science.

Development of Geometry-Controlled All-Orthogonal BODIPY Trimers for Photodynamic Therapy and Phototheragnosis.

We have established an easy synthetic protocol for selectively developing all-orthogonal BODIPY trimers with unprecedented geometries on the basis of selecting methyl oxidation versus electrophilic formylation of key dimeric precursors. Photophysical characterization together with biological assays unraveled the most suitable BODIPY-BODIPY geometrical arrangements within the trimer, forcing them to serve as molecular platforms for the development of new, advanced heavy-atom-free photosensitizers for photodynamic therapy and phototheragnosis.

BINOL blocks as accessible triplet state modulators in BODIPY dyes.

BINOL moieties of different electronic demand are useful blocks for enabling the photo-production and modulation of triplet excited states in readily-accesible BINOL-based O-BODIPY dyes from standard F-BODIPY precursors. The rapid and rational development of smarter triplet-enabling BODIPY dyes on the basis of this strategy (e.g., TADF biomarker 4a or room temperature phosphor 4g) paves the way for advancing photonic applications based on organic triplet photosensitizers.