Synthesis of π-expanded BODIPYs and their fluorescent properties in the visible-near-infrared region

A series of π-expanded boron-dipyrromethenes (BODIPYs) fused with aromatic rings at β,β-positions, such as benzene, acenaphthylene, and benzofluoranthene were prepared by the reaction of BF₃·OEt₂ with bicyclo[2.2.2]octadiene-fused dipyrromethene and the subsequent retro Diels-Alder reaction. These BODIPYs exhibited the absorptions and the fluorescence emissions over wide range of visible-near-infrared region at 500-800 nm. BODIPYs composed of two fluorantho[8,9-f]isoindoles absorbed and emitted at red-region over 750 nm with absolute fluorescence quantum yield (Φ_f) of ca. 0.3, although they are unstable under air in room light. BODIPY composed fluorantho[8,9-f]isoindole and acenaphtho[1,2-c]pyrrole was stable and showed a bright fluorescence emission at 695 nm with high Φ_f of 0.70.     

Synthesis and chiroptical properties of phenanthrene-fused N2O-type BODIPYs

A series of phenanthrene-fused N₂O-type boron-dipyrrin complexes (BODIPYs) with various substituents were synthesized. The synthesized BODIPYs show light absorption and emission in the red to near-infrared region due to their extended π-system. Furthermore, the first optical resolution of the N₂O-type BODIPY was achieved using the phenyl-substituted complex. The separated enantiomers are stable to racemization at room temperature, and exhibited a Cotton effect in the deep-red region.     

Visible‐Light Photoactive,Highly Efficient Triplet Sensitizers Based on Iodinated Aza‐BODIPYs: Synthesis,Photophysics and Redox Properties

A series of novel iodinated NO₂‐substituted aza‐BODIPYs have been synthesized and characterized. Highly desirable photophysical and photochemical properties were induced in NO₂‐substituted aza‐BODIPYs by iodination of the pyrrole rings. In particular, high values of singlet oxygen quantum yields (Φ_Δ) ranging from 0.79 to 0.85 were measured. The photooxygenation process proceeds via a Type II mechanism under the experimental conditions applied. The compounds studied exhibited an absorption band within the so‐called “therapeutic window”, with λ_max located between 645 nm to 672 nm. They were non‐fluorescent at room temperature with excited singlet‐state lifetimes within the picosecond range as measured by femtosecond transient absorption. Nanosecond laser flash photolysis experiments revealed T₁→T_n absorption spanning from ca. 400 nm to ca. 500 nm and allowed determination of the triplet‐state lifetimes. The estimated triplet lifetimes (τ_T) in deaerated acetonitrile ranged between 2.74 μs and 3.50 μs. As estimated by CV/DPV measurements, all iodinated aza‐BODIPYs studied exhibited one irreversible oxidation and two quasi‐reversible reductions processes. Estimation of the E_HOMO gave the value of ?6.06 to ?6.26 eV while the E_LUMO was found to be located at ca. ?4.6 eV. Thermogravimetric (TGA) analysis revealed that iodinated aza‐BODIPYs were stable up to approximately 300 °C. All compounds studied exhibit high photostability in toluene solution.     

π-Fused bis-BODIPY as a candidate for NIR dyes

Benzene-fused bis-(borondipyrromethene)s (bis-BODIPYs) were synthesized by retro-Diels-Alder reaction of the corresponding bicyclo[2.2.2]octadiene-fused (BCOD-fused) bis-BODIPYs, which were, in turn, prepared from 4,8-ethano-4,8-dihydropyrrolo[3,4-f]isoindole derivatives. The π-fused bis-BODIPY chromophores were designed to show intensive absorption and strong fluorescence in the near-infrared region and not to have any strong absorption in the visible region. A 6,10-dibora-5a,6a,9a,10a-tetraaza-s-indaceno[2,3-b:6,5-b']difluorene derivative (syn-bis-benzoBODIPY) obtained by a thermal retro-Diels-Alder reaction of the corresponding BCOD-fused BODIPY dimer has strong absorption and emission bands at 775 and 781 nm, respectively. The absolute quantum yield is 0.36. The absorption is more than 5.0 times stronger than other absorptions observed in the visible region. In the case of 6,15-dibora-5a,6a,14a,15a-tetraaza-s-indaceno[2,3-b:6,7-b']difluorene derivatives (anti-bis-benzoBODIPY), the absorption and emission maxima exceed 840 nm.     

Synthesis of Water‐Soluble Red‐Emitting Thienyl–BODIPYs and Bovine Serum Albumin Labeling

Thesynthesis of three red‐emitting and water‐soluble thienyl‐BODIPYs has beenachieved. The trimethyl(propargyl)ammonium group was chosen as a vector forwater solubility. One or two cationic arms were introduced either on the2‐position of the thienyl unit or on the 4‐position on the boron atom. Thesedyes have pronounced absorption around 600 nm and intense emission at 650 nmwith quantum yield of about 60% in water. Grafting of such BODIPYs via a flexible arm to BSA is veryefficient, allowing attachment of 1 to 30 labels in a controlled manner.  Very strong fluorescence (quantum yield 56%)without aggregation of the dye at a low loading ratio (1:5 BSA/label) in PBSbuffer is measured.     

Synthesis of π-expanded O-chelated boron-dipyrromethene as an NIR dye

A π-expanded BODIPY dye with an intramolecular boronate skeleton was synthesized by retro Diels-Alder reaction of the bicyclo[2.2.2]octadiene (BCOD)-fused BODIPY and the subsequent O-chelation. The photophysical and electrochemical properties were examined by UV-vis, fluorescence, CV measurements, and DFT calculation. This BODIPY exhibited the absorption and emission over a visible-NIR region at 600-850 nm. O-chelated BODIPY showed a bathocromic shift compared to F-BODIPYs. This dye showed a bright fluorescence emission at 733 nm with the high Φ value of 0.58.     

Synthesis, computational modeling, and properties of benzo-appended BODIPYs

A series of new functionalized mono- and dibenzo-appended BODIPY dyes were synthesized from a common tetrahydroisoindole precursor following two different synthetic routes. Route?A involved the assembly of the BODIPY core prior to aromatization, while in Route?B the aromatization step was performed first. In general, Route?A gave higher yields of the target dibenzo-BODIPYs, due to the ease of aromatization of the BODIPYs compared with the corresponding dipyrromethenes, probably due to their higher stability under the oxidative conditions (2,3-dichloro-5,6-dicyano-1,4-benzoquinone in refluxing toluene). However, due to the slow oxidation of highly electron-deficient BODIPY 3?c bearing a meso-C(6)F(5) group, dibenzo-BODIPY 4?c was obtained, in 35?% overall from dipyrromethane, only by Route?B. Computational calculations performed at the 6-31G(d,p) level are in agreement with the experimental results, showing similar relative energies for all reaction intermediates in both routes. In addition, BODIPY 3?c had the highest molecular electrostatic potential (MEPN), confirming its high electron deficiency and consequent resistance toward oxidation. X-ray analyses of eight BODIPYs and several intermediates show that benzannulation further enhances the planarity of these systems. The π-extended BODIPYs show strong red-shifted absorptions and emissions, about 50-60?nm per benzoannulated ring, at 589-658 and 596-680?nm, respectively. In particular, db-BODIPY 4?c bearing a meso-C(6)F(5) group showed the longest λ(max) of absorption and emission, along with the lowest fluorescence quantum yield (0.31 in CH(2)Cl(2)); on the other hand monobenzo-BODIPY 8 showed the highest quantum yield (0.99) of this series. Cellular investigations using human carcinoma HEp2 cells revealed high plasma membrane permeability for all dibenzo-BODIPYs, low dark- and photo-cytotoxicities and intracellular localization in the cell endoplasmic reticulum, in addition to other organelles. Our studies indicate that benzo-appended BODIPYs, in particular the highly stable meso-substituted BODIPYs, are promising fluorophores for bioimaging applications.     

Synthesis and application of Vis/NIR dialkylaminophenylbuta-1, 3-dienyl borondipyrromethene dyes

Mono- and bis-dialkylaminophenylbuta-1,3-dienyl boron-dipyrromethenes(BODIPYs) 1–12 were synthesized in 36%–42% yields by a Knoevenagel-type condensation. The absorption and emission maxima(labs= 614–739 nm; lem= 655–776 nm in CHCl3) of 1–12 covered from the visible to the nearinfrared region. Probe 1 was ratiometric Vis p H probes. Such probe was almost non-fluorescent. Upon the protonation of the tertiary amine function of 1, the strong fluorescence(Φf= 0.97) was released and the florescence intensity was dramatically increased by one thousand folds. The sharp isosbestic points were discovered at 590 nm, which was a ratiometric p H probe.     

Synthesis,Structure, and Optical Studies of Donor–Acceptor‐Type Near‐Infrared (NIR) Aza–Boron‐Dipyrromethene (BODIPY) Dyes

Six donor–acceptor‐type near‐infrared (NIR) aza–boron‐dipyrromethene (BODIPY) dyes and their corresponding aza–dipyrrins were designed and synthesized. The donor moieties at the 1,7‐positions of the aza–BODIPY core were varied from naphthyl to N‐phenylcarbazole to N‐butylcarbazole. The 3,5‐positions were also substituted with phenyl or thienyl groups in the aza–BODIPYs. Photophysical, electrochemical, and computational studies were carried out. The absorption and emission spectra of aza–BODIPYs were significantly redshifted (≈100 nm) relative to the parent tetraphenylaza–BODIPY. Fluorescence studies suggested effective energy transfer (up to 93 %) from donor groups to the aza–BODIPY core in all of the compounds under study. Time‐dependent (TD)‐DFT studies indicated effective electronic interactions between energy donor groups and aza–dipyrrin unit in all the aza–BODIPYs studied. The HOMO–LUMO gap (ΔE) calculated from cyclic voltammetry data was found to be lower for six aza–BODIPYs relative to their corresponding aza–dipyrrins.     

Highly Pure Synthesis,Spectral Assignments,and Two‐Photon Properties of Cruciform Porphyrin Pentamers Fused with Benzene Units

Tetrameric porphyrin formation of 2‐hydroxymethylpyrrole fused with porphyrins through a bicyclo[2.2.2]octadiene unit gave bicyclo[2.2.2]octadiene‐fused porphyrin pentamers. Thermal conversion of the pentamers gave fully π‐conjugated cruciform porphyrin pentamers fused with benzene units in quantitative yields. UV/Vis spectra of fully π‐conjugated porphyrin pentamers showed one very strong Q absorption and were quite different from those of usual porphyrins. From TD‐DFT calculations, the HOMO level is 0.49 eV higher than the HOMO?1 level. The LUMO and LUMO+1 levels are very close and are lower by more than 0.27 eV than those of other unoccupied MOs. The strong Q absorption was interpreted as two mutually orthogonal single‐electron transitions (683 nm: 86 %, HOMO→LUMO; 680 nm: 86 %, HOMO→LUMO+1). The two‐photon absorption (TPA) cross section value (σ⁽²⁾) of the benzene‐fused porphyrin pentamer was estimated to be 3900 GM at 1500 nm, which is strongly correlated with a cruciform molecular structure with multidirectional π‐conjugation pathways.     

Development of non-symmetric thiophene-fused BODIPYs

A series of non-symmetric BODIPYs containing thieno[3,2-b]pyrrole moiety were synthesized in 21-63% yields. The absorption and emission maxima covered from the visible green to red region (λ_abs=532-647 nm; λ_em=547-664 nm; Φ_f=0.19-0.45). X-ray analysis indicated that the S-C bond lengths were shorter than those of thienopyrrole and thienohelicene by 0.03-0.05 Å. The crystal packing pattern suggested that strong π-π interaction, intermolecular C-H?F interaction, and weak S?π interaction existed. The tunable emission was achieved by structure modifications. Oxidation of BODIPY (λ_em=547 nm) with m-CPBA generated thiophene-1,1-dioxide derived BODIPY (λ_em=528 nm). Knoevenagel-type condensation of BODIPY with N,N-dimethylaminobenzaldehyde led to BODIPY (λ_em=693 nm) with extended conjugation.     

Rational design of shortwave infrared (SWIR) fluorescence probe: Cooperation of ICT and ESIPT processes for sensing endogenous cysteine

Cysteine is well-known to be an important biothiol and related to many diseases. However, the in vivo detection of endogenous cysteine still suffers from lacking small-molecule fluorophores with both excitation and emission in the near-infrared (650-900 nm)/shortwave-infrared region. Herein, we report a molecular engineering strategy for shortwave infrared (SWIR, 900-1700 nm) sensing of cysteine, which integrated an excited-state intermolecular proton transfer (ESIPT) building block into the intramolecular charge transfer (ICT) scaffold. The obtained novel fluorophore SH-OH displays a maximum absorption at the NIR region, and emission at the SWIR region. We introduce the cysteine-recognition moiety to SH-OH structure, and demonstrate sensing of endogenous cysteine in living animals, using the SWIR emission as a reliable off-on fluorescence signal. This fluorophore design strategy of cooperation of ICT and ESIPT processes expands the in vivo sensing toolbox for accurate analysis in clinical applications.     

Autocatalytic polymerization of selenium/polypyrrole nanocomposites as functional theranostic agents for multi-spectral photoacoustic imaging and photothermal therapy of tumor

The synchronization of diagnosis and treatment is a new trend in cancer treatment. Photoacoustic imaging (PAI) and photothermal therapy (PTT) are recognized as one of the perfect combinations. The autocatalytic polymerization of selenium/polypyrrole (Se@PPy) nanocomposites with a wide-absorption band at near-infrared region (NIR, 800 nm) has been developed in this paper. The wide optical absorption characteristics enable Se@PPy nanocomposites to achieve multi-spectral PAI. Ex vivo experiments show desirable photoacoustic ability of the Se@PPy nanocomposites at wavelengths ranging from 700 nm to 900 nm, which is better than that of commercial indocyanine green (ICG). Se@PPy nanocomposites have high photothermal conversion efficiency up to 36.3% as well as excellent photo-thermal stability. In vitro cytotoxicity test demonstrates that the Se@PPy nanocomposites have good bio-safety. Furthermore, the feasibility of Se@PPy nanocomposites for enhancing multi-spectral PAI guided PTT was verified on 4T1 tumor-bearing nude mice. Our results indicate that Se@PPy nanocomposites could be used as an effective theranostic agent for near-infrared light-mediated PAI and PTT of tumor.     

Synthesis and electrochromic properties of polyimides with pendent benzimidazole and triphenylamine units

Five novel near-infrared electrochromic aromatic polyimides(PIs) with pendent benzimidazole group were synthesized from 4,4'-diamino-4'-(1-benzylbenzimidazol-2-yl)triphenylamine(named as DBBT) with five different dianhydrides via two-step polymerization process, respectively. The maximum UV-Vis absorption bands of these PIs locate at about 335 nm for solid films due to the π-π* transitions. A reversible pair of distinct redox peaks, that were associated with a noticeable color change from original yellow to blue, was observed in the cyclic voltammetry(CV) test. A new absorption peak emerged at 847 nm in near-infrared(NIR) region with increasing voltage in UV-Vis-NIR spectrum, which indicates that PI can be used as NIR electrochromic material. These novel PIs have good electrochemical stability, appropriate energy levels for the highest occupied molecular orbital(HOMO) and the lowest unoccupied molecular orbital(LUMO), in the range of-5.17 e V to-5.20 e V and-2.14 e V to-2.26 e V(versus the vacuum level) determined by cyclic voltammetry method. These values basically consisted with the results of quantum chemical calculation. These polyimides can be used as novel electrochromic and hole transportation materials.     

Development of mono- and di-AcO substituted BODIPYs on the boron center

Mono- and di-AcO substituted BODIPYs (1 and 2) were synthesized from TM-BDP. The structures of 1 and 2 were supported by single crystal X-ray analysis. Both 1 and 2 possess a large absorption coefficient, high fluorescence quantum yield, and high light stability. Compound 2 has much improved water solubility which is highly desirable for biological applications. Theoretical calculation supports our observations in X-ray analysis, absorption, and cyclic voltammetry.     

Asymmetric Donor–π‐Acceptor‐Type Benzo‐Fused Aza‐BODIPYs: Facile Synthesis and Colorimetric Properties

Novel aza‐diisoindolylmethene and their BF₂‐chelating complexes (benzo‐fused aza‐BODIPYs) were synthesized on a large scale and in a facile manner from phthalonitrile in tBuOK‐DMF solution. The unique asymmetric donor–π‐acceptor structure facilitates B? N bond detachment in the presence of trifluoroacetic acid (TFA) in dichloromethane, resulting in sharp color change from red to colorless, with over 250 nm hypsochromic shift in the absorption maximum. This colorimetric process can be reversed by adding a very small amount of proton‐accepting solvents or compounds. A ¹H and ¹¹B NMR spectroscopy study and also density functional theory (DFT) calculations suggest that TFA‐induced B? N bond cleavage may disrupt the whole π‐conjugation of the BODIPY molecule, resulting in significant colorimetric behavior.     

Near-infrared absorbing (>700 nm) aza-BODIPYs by freezing the rotation of the aryl groups

The typical aza-BODIPYs in the dye family are known for bright fluorescence, excellent stability, and tunable absorption wavelengths. Hence, these dyes are attracting the increasing attention. Aza-BODIPYs having the maxima absorption in the near-infrared (NIR) region (650–900 nm) are very favorable for bioimaging in vivo due to the less photo-damage, deeper tissue penetration, and less interference from background auto-fluorescence by biomolecules in the living systems. Many strategies have been employed to modify the structures of the aza-BODIPY core to provide the NIR absorbing dyes. Among these, the most effective method is the fusion of the aromatic rings in aza-BODIPY system. This review allsidedly summarizes the recent development of ring-fused aza-BODIPY dyes (λ_abs > 700 nm) focusing on the design, synthesis, and potential applications in the NIR region since 2002.     

Substituents modification of meso-aryl BODIPYs for tuning photophysical properties

We successfully synthesized eight meso-aryl BODIPYs with 2,6-diethyl- or 1,2,6,7-tetraethyl substituents and characterized their photophysical properties. The steric hindrance resulting from the phenolic group in the meso-aryl moiety and the ethyl groups on the BODIPY core affected the synthesis of dipyrromethanes as an intermediate as well as the UV–Vis absorption and fluorescence emission of the BODIPYs due to the constrained rotation of the aryl ring. The potential use of the meso-hydroxyphenyl BODIPY as a pH sensor was also shown by the pH-dependent fluorescence emissions.     

New pyrrolo[3,2-b]pyrrole derivatives with multiple-acceptor substitution: Efficient fluorescent emission and near-infrared two-photon absorption

Two new D-π-A organic chromophores, 1,2,4,5-tetra(4-cyanophenyl)pyrrolo[3,2-b]pyrrole (4CNPP) and 1,2,3,4,5,6-hexa(4-cyanophenyl)pyrrolo[3,2-b]pyrrole (6CNPP), were developed by modifying the electron-rich pyrrolo[3,2-b]pyrrole (PP) unit with four and six 4-cyanophenyls respectively. The compounds exhibited bright blue emissions in low- to high-polarity solvents, with high Ф_fs of 88–90% in toluene, as well as impressive two-photon absorption cross-sections at the near-infrared (NIR) 700?nm.     

Water-soluble NIR fluorescent probes based on squaraine and their application for protein labeling.

Water-soluble near-infrared (NIR) fluorescent labeling probes, named KSQ-3 and -4, which are based on a squaraine backbone, were synthesized and applied to biological labeling. The presented results demonstrate that the large, planar and hydrophobic squaraine dye becomes fully soluble in aqueous solution by the introduction of several sulfo group terminated alkyl substituents. Especially KSQ-4, which is substituted with four sulfo groups, exhibited perfect water solubility and significant fluorescence emission at the NIR region (817 nm) in the presence of bovine serum albumin (BSA). BSA was covalently labeled with KSQ-4, and the conjugate showed a strong absorption peak at 787 nm, which indicates compatibility with commercially available NIR laser diodes used for exciting the fluorophore. Furthermore, strong fluorescence emission was observed at 812 nm (phi = 0.08).