Synthesis of Fluorescent Pyrrolo[1,2-a]pyrimidines from Fischer Carbene Complexes as Building Blocks.

A novel synthetic methodology is reported for the synthesis of fluorescent pyrrolo[1,2-a]pyrimidines. Fischer carbene complexes served as the synthetic platform for (3+3) cyclization to form the heterocyclic moiety. The reaction process furnished two products, their ratio being modulated by the metal, base, and solvent. The selectivity exhibited was studied by analyzing the potential energy surface with density functional theory tools. The photophysical properties of absorption and emission were also evaluated. The dyes absorbed at wavelengths of 240-440 nm, depending on the substituents. The maximum emission wavelength was in the range of 470-513 nm, with quantum yields of 0.36-1.0 and a high Stokes shift range of 75-226 nm.

Extended BODIPYs as Red-NIR Laser Radiation Sources with Emission from 610 nm to 750 nm.

Herein, we report the synthetic access to a set of π-extended BODIPYs featuring a penta-arylated (phenyl and/or thiophene) dipyrrin framework. We take advantage of the full chemoselective control of 8-methylthio-2,3,5,6-tetrabromoBODIPY when we conduct the Liebeskind-Srogl cross-coupling (LSCC) to functionalize exclusively the meso-position, followed by the tetra-Suzuki reaction to arylate the halogenated sites. All these laser dyes display absorption and emission bands in the red edge of the visible spectrum reaching the near-infrared with thiophene functionalization. The emission efficiency, both fluorescence and laser, of the polyphenylBODIPYs can be enhanced upon decoration of the peripheral phenyls with electron donor/acceptor groups at para positions. Alternatively, the polythiopheneBODIPYs show an astonishing laser performance despite the charge transfer character of the emitting state. Therefore, these BODIPYs are suitable as a palette of stable and bright laser sources covering the spectral region from 610 nm to 750 nm.

Synthesis of Polysubstituted Symmetrical BODIPYs via Fischer Carbene Complexes: Theoretical, Photophysical and Electrochemical Evaluation.

A series of new symmetrical highly substituted BODIPYs 6 a-l was synthesized through a prefunctionalization approach in 35 %-89 % yields from the pyrrole core. This strategy allowed modulation of the substituents at the different positions based on the choice of Fischer's alkynyl carbenes, oxazolones and aldehydes used as precursors. The substituent variation at positions 2, 6, 3 and 5 had the greatest effect on the modulation of their photophysical properties such as absorption (λabs ) and emission (λem ) wavelengths, extinction coefficient (ϵ), quantum yields (ϕ), Stokes shifts (Δν), fluorescence decay, radiative (krad ) and non-radiative (knr ) constants and the CIE 1931 coordinates. Theoretical calculations allowed to corroborate the effect of the substituents of meso-position on the modification of the dihedral angles. Cyclic voltammetry studies revealed that the BODIPY series presents similar redox potential behavior, being electrochemically active even in successive cycles, which suggests that transport by diffusion is the dominant process.

Organocatalytic Cascade Reactions for the Diversification of Thiopyrano-Piperidone Fused Rings Utilizing Trienamine Activation.

An aminocatalytic privileged diversity-oriented synthesis (ApDOS) strategy utilizing trienamine catalysis for the construction of diverse and complex thiopyrans-piperidone fused rings through a thia-Diels-Alder/nucleophilic ring-closing sequence by using dithioamides as activated heterodienophiles is reported. Following this strategy, a super cascade reaction to assemble nine fused rings can be achieved by employing a bis-dithioamide. Additionally, by linking an indole moiety on the dithioamide, a Pictet-Spengler type reaction can be promoted once the cascade sequence has been achieved, leading to more complex penta- hexa- and heptacyclic fused ring derivatives in a one-pot process. This investigation opens new perspectives for the synthesis of a new class of complex and diverse thiopyrans that contribute to populate new relevant regions in the chemical space.

Effect of the substituents of new coumarin-imidazo[1,2-a]heterocyclic-3-acrylate derivatives on nonlinear optical properties: a combined experimental-theoretical approach.

A series of new coumarin-imidazo[1,2-a]heterocyclic-3-acrylate derivatives 7a-h were synthesized by the Heck reaction between the corresponding 3-(imidazo[1,2-a]pyrimidines)-(2-yl)-2H-chromen-2-ones 4a-e and methyl acrylate in 45-87% yields. The effect of the distinct substituents on third-order nonlinear optical properties was examined, experimentally measuring their nonlinear refractive indexes by the Z-scan technique. Density functional theory and time-dependent density functional theory were utilized with the B3LYP, CAM-B3LYP, PBE (PBEPBE), and M062X functionals on Gaussian09 software to calculate the vertical excitation, relaxation of the brightest excited states, conformation, HOMO-LUMO gaps, oscillator strength, polarizability, and hyperpolarizabilities of all derivatives. Although all acrylates showed a nonlinear response at a certain level of power, the compounds bearing a diethylamino electron-donating group exhibited higher nonlinear refractive index values (∼10-9 cm2 W-1), which is in agreement with the trend in the computational calculations of the first and second hyperpolarization. According to the structural analysis, the electron-withdrawing group (acrylate) is mainly responsible for the loss of coplanarity because of increasing the dihedral angle between the coumarin and imidazo[1,2-a]heterocyclic moieties (to 39.1°). On the other hand, the unsubstituted compound 4a presented the greatest nonlinearity due to its almost coplanar structure (n2 ∼ 10-8 cm2 W-1), highlighting the importance of this feature.

A static and dynamic NMR study of 10-hydrazino-BODIPY.

10-Hydrazino-BODIPY, BoNHNH2 , presents slow rotation about the C10-NH bond that results in anisochronous 1 H and 13 C NMR signals. The assignment of the different signals has been made using traditional two-dimensional methods as well as spin-spin coupling constants and confirmed by DFT calculations (B3LYP) using the 6-311++G(d,p) basis set. The rotational barrier has been determined in three pairs of proton signals and compared with the calculated barrier.

Ready Access to Molecular Rotors Based on Boron Dipyrromethene Dyes-Coumarin Dyads Featuring Broadband Absorption.

Herein we report on a straightforward access method for boron dipyrromethene dyes (BODIPYs)-coumarin hybrids linked through their respective 8- and 6- positions, with wide functionalization of the coumarin fragment, using salicylaldehyde as a versatile building block. The computationally-assisted photophysical study unveils broadband absorption upon proper functionalization of the coumarin, as well as the key role of the conformational freedom of the coumarin appended at the meso position of the BODIPY. Such free motion almost suppresses the fluorescence signal, but enables us to apply these dyads as molecular rotors to monitor the surrounding microviscosity.

Synthetic Approach to Readily Accessible Benzofuran-Fused Borondipyrromethenes as Red-Emitting Laser Dyes.

We took advantage of the chemoselective meso-functionalization of 2,3,5,6-tetrabromo-8-methylthioBODIPY 6 to prepare a series of 2,3,5,6-tetrabromo-8-arylBODIPY derivatives suitable for SNAr substitution reactions with phenols exclusively at positions 3 and 5. Pd(0)-catalyzed intramolecular arylation reaction ensued on the remaining brominated positions 2 and 6 to give a new family of benzofuran-fused BODIPY dyes. This method utilizes readily available starting materials and allows for the preparation of the title compounds with excellent functional group tolerance. Moreover, it was demonstrated that the methodology described herein is amenable for the incorporation of biomolecules. The photophysical and lasing properties of the benzofuran-fused BODIPY dyes were thoroughly analyzed with the aid of electrochemical measurements and quantum mechanical simulations. These dyes show bright and intriguing emission (both fluorescence and laser) toward the red edge of the visible spectrum with remarkable tolerance under strong and continuous irradiation.

Development of a Fluorescent Bodipy Probe for Visualization of the Serotonin 5-HT1A Receptor in Native Cells of the Immune System.

Serotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions.

Fully Functionalizable ß,ß'-BODIPY Dimer: Synthesis, Structure, and Photophysical Signatures.

The versatility in the synthesis of BODIPY derivatives in terms of functionalization is further demonstrated. In particular, in this work ß-ß'-BODIPY dimers with varied functional groups in the meso positions were synthesized in very efficient yields and short reaction times from a single platform. A photophysical study was carried out in all of the compounds. The resultant dimers show absorption bands at around 600 nm as a consequence of electronically coupled monomers disposed with a dihedral angle of around 30°, which is supported by theoretical simulations. The emission properties of these molecules are distinguished by the appearance of an ICT state as the polarity of the solvent increases.

Adapting BODIPYs to singlet oxygen production on silica nanoparticles.

A modified Stöber method is used to synthesize spherical core-shell silica nanoparticles (NPs) with an external surface functionalized by amino groups and with an average size around 50 nm. Fluorescent dyes and photosensitizers of singlet oxygen were fixed, either separately or conjointly, respectively in the core or in the shell. Rhodamines were encapsulated in the core with relatively high fluorescence quantum yields (Φfl ≥ 0.3), allowing fluorescence tracking of the particles. Various photosensitizers of singlet oxygen (PS) were covalenty coupled to the shell, allowing singlet oxygen production. The stability of NP suspensions strongly deteriorated upon grafting the PS, affecting their apparent singlet oxygen quantum yields. Agglomeration of NPs depends both on the type and on the amount of grafted photosensitizer. New, lab-made, halogenated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPY) grafted to the NPs achieved higher singlet oxygen quantum yields (ΦΔ âˆ¼ 0.35-0.40) than Rose Bengal (RB) grafted NPs (ΦΔ âˆ¼ 0.10-0.27). Finally, we combined both fluorescence and PS functions in the same NP, namely a rhodamine in the silica core and a BODIPY or RB grafted in the shell, achieving the performance Φfl ∼ 0.10-0.20, ΦΔ âˆ¼ 0.16-0.25 with a single excitation wavelength. Thus, proper choice of the dyes, of their concentrations inside and on the NPs and the grafting method enables fine-tuning of singlet oxygen production and fluorescence emission.

Exploring viscosity, polarity and temperature sensitivity of BODIPY-based molecular rotors.

Microviscosity is a key parameter controlling the rate of diffusion and reactions on the microscale. One of the most convenient tools for measuring microviscosity is by fluorescent viscosity sensors termed 'molecular rotors'. BODIPY-based molecular rotors in particular proved extremely useful in combination with fluorescence lifetime imaging microscopy, for providing quantitative viscosity maps of living cells as well as measuring dynamic changes in viscosity over time. In this work, we investigate several new BODIPY-based molecular rotors with the aim of improving on the current viscosity sensing capabilities and understanding how the structure of the fluorophore is related to its function. We demonstrate that due to subtle structural changes, BODIPY-based molecular rotors may become sensitive to temperature and polarity of their environment, as well as to viscosity, and provide a photophysical model explaining the nature of this sensitivity. Our data suggests that a thorough understanding of the photophysics of any new molecular rotor, in environments of different viscosity, temperature and polarity, is a must before moving on to applications in viscosity sensing.

Near-IR BODIPY Dyes à la Carte-Programmed Orthogonal Functionalization of Rationally Designed Building Blocks.

Herein, we report the synthesis of polyfunctional BODIPY building blocks suitable to be subjected to several reaction sequences with complete chemoselectivity, thereby allowing the preparation of complex BODIPY derivatives in a versatile and programmable manner. The reactions included the Liebeskind-Srogl cross-coupling reaction (LSCC), nucleophilic aromatic substitution (SN Ar), Suzuki, Sonogashira, and Stille couplings, and a desulfitative reduction of the MeS group. This novel synthetic protocol is a powerful route to design a library of compounds with tailored photophysical properties for advanced applications. In this context, it is noteworthy that it offers a straightforward and cost-effective strategy to shift the BODIPY emission deep into the near-infrared spectral region while retaining high fluorescence quantum yields as well as highly efficient and stable laser action. These new dyes outperform the lasing behaviour of dyes considered as benchmarks over the red spectral region, overcoming the important drawbacks associated with these commercial laser dyes, namely low absorption at the standard pump wavelengths (355 and 532 nm) and/or poor photostability.

FormylBODIPYs: Privileged Building Blocks for Multicomponent Reactions. The Case of the Passerini Reaction.

Eleven formyl-containing BODIPY dyes were prepared by means of either the Liebeskind-Srogl cross-coupling reaction or the Vilsmeier reaction. These dyes were used as components in the Passerini reaction to give highly substituted BODIPY dyes. A joined spectroscopic and theoretical characterization of the synthesized compounds was conducted to unravel the impact of the structural rigidity/flexibility on the photophysical signatures. These dyes were tested as fluorescent trackers for phagocytosis. Additionally, they proved to be useful to stain different blood cells with an intense and stable signal at a very low exposure time.

Straightforward synthetic protocol for the introduction of stabilized C†nucleophiles in the BODIPY core for advanced sensing and photonic applications.

A straightforward synthetic protocol to directly incorporate stabilized 1,3-dicarbonyl C nucleophiles to the meso position of BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) is reported. Soft nucleophiles generated by deprotonation of 1,3-dicarbonyl derivatives smoothly displace the 8-methylthio group from 8-(methylthio)BODIPY analogues in the presence of Cu(I) thiophenecarboxylate in stoichiometric amounts at room temperature. Seven highly fluorescent new derivatives are prepared with varying yields (20-92%) in short reaction times (5-30 min). The excellent photophysical properties of the new dyes allow focusing on applications never analyzed before for BODIPYs substituted with stabilized C nucleophiles such as pH sensors and lasers in liquid and solid state, highlighting the relevance of the synthetic protocol described in the present work. The attainment of these dyes, with strong UV absorption and highly efficient and stable laser emission in the green spectral region, concerns to one of the greatest challenges in the ongoing development of advanced photonic materials with relevant applications. In fact, organic dyes with emission in the green are the only ones that allow, by frequency-doubling processes, the generation of tunable ultraviolet (250-350 nm) radiation, with ultra-short pulses.

Scope and Limitations of the Liebeskind-Srogl Cross-Coupling Reactions Involving the Biellmann BODIPY.

Several new examples of meso-(het)arylBODIPY were prepared via the Liebeskind-Srogl (L-S) cross-coupling reaction of the Biellmann BODIPYs (1a,b) and aryl- and heteroarylboronic acids in good to excellent yield. It was shown that this reaction could be carried out under microwave heating to shorten reaction times and/or increase the yield. It was illustrated that organostannanes also participate in the L-S reaction to give the corresponding BODIPY analogues in short reaction times and also with good to excellent yields. We analyze the role of the substituent at the sensitive meso position in the photophysical signatures of these compounds. In particular, the rotational motion of the aryl ring and the electron donor ability of the anchored moieties rule the nonradiative pathways and, hence, have a deep impact in the fluorescence efficiency.

Unprecedented one-pot sequential thiolate substitutions under mild conditions leading to a red emissive BODIPY dye 3,5,8-tris(PhS)-BODIPY.

The simple reaction of phenylthiol with 8-MeS-BODIPY (1) in dichloromethane was readily accomplished to form 8-PhS-BODIPY (2). If the reaction is performed in THF 3,8-bis(phenylthio)-BODIPY (3) and 3,5,8-tris(phenylthio)-BODIPY (4) are sequentially formed in an unprecedented reaction. This provides a simple new methodology for the introduction of the phenylthio-moiety in the 3- and 5-positions. Alkyl thiols do not form multi-thiolated products under identical conditions, as exemplified using EtSH, where only 8-EtS-BODIPY (5) is formed.

Blue-to-orange color-tunable laser emission from tailored boron-dipyrromethene dyes.

A series of meso-substituted boron-bipyrromethene (BODIPY) dyes are synthesized and their laser and photophysical properties systematically studied. Laser emission covering a wide visible spectral region (from blue to orange) is obtained by just changing the electron donor character of the heteroatom at position 8. The additional presence of methyl groups at positions 3 and 5 results in dyes with a photostability similar to that of the unsubstituted dye but with much improved efficiency. Correlation of the lasing properties of the different dyes to their photophysical properties provides inklings to define synthetic strategies of new BODIPY dyes with enhanced efficiency and modulated wavelength emission over the visible spectral region.

8-Amino-BODIPYs: structural variation, solvent-dependent emission, and VT NMR spectroscopic properties of 8-R2N-BODIPY.

New 8-NR2-BODIPYs, R2 = H(i)Pr (3a), H(i)Bu (3b), and Et2 (4), are reported. Restricted rotation about the C8-N bond in such molecules has been observed for the first time (3a and 3b) and evaluated using VT NMR. The fluorophores 3a and 3b are blue emitters, and the efficiency of the emission is closely related to the polarity of the solvent, e.g., hexane > toluene > DCM > THF > MeOH > H2O, an effect also noted by emission variation in alcohol solvents H(CH2)nOH, n = 1-6. In mixed-solvent systems, addition of 10-15% of the more polar solvent results in transformation of the emission properties to those of the bulk polar solvent. Compound 4 has zero emission in all solvents. The crystal structures of 3a, 3b, and 4 are reported, along with that of the parent 8-NH2-BODIPY (2). Compounds 2, 3a, and 3b exhibit trigonal planar N atoms which are coplanar with the BODIPY core; 4 exhibits a very significant distortion that breaks the planarity of the extended BODIPY π system due to the steric impact of the two ethyl groups, an observation that explains the lack of emission for 4.

8-Alkoxy- and 8-aryloxy-BODIPYs: straightforward fluorescent tagging of alcohols and phenols.

We demonstrate herein that both alcohols and phenols can be tagged with a BODIPY (borondipyrromethene) moiety to yield highly fluorescent products. Thus, 8-(methylthio)-BODIPY (1) undergoes an S(N)Ar-type reaction with a host of alcohols and phenols in the presence of a base and a Cu(I) additive. The BODIPY dyes bearing alkoxy or nonfunctionalized phenoxy moieties are characterized by a highly efficient fluorescence emission, regardless of the media, in the blue-green part of the visible region. Complementary to this, the presence of electron-donor groups at the aryl ring leads to an intramolecular charge-transfer process, which quenches the fluorescence mainly in polar media. In addition to simple alcohols and phenols, four natural products (eugenol, menthol, cholesterol, and estrone) were labeled in a simple fashion. X-ray structures of the cholesterol and estrone derivatives are discussed. In fact, the BODIPY bearing cholesterol stands out as a bright fluorescence biological marker.