Synthesis, Computational Modeling, and Properties of Benzo‐Appended BODIPYs

Abstract

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.

Spectroscopic, computational modeling and cytotoxicity of a series of meso-phenyl and meso-thienyl-BODIPYs

“…13,15 These meso -aryl BODIPYs were synthesized to investigate the effects of halogenation and the nature of the meso -aryl groups on the photophysical and cytotoxic properties of the BODIPYs. Meso -Substitution has been observed to increase the photostability of the BODIPY 47,48 and iodination at the 2,6-positions is reported to enhance intersystem crossing by the ‘heavy atom effect,’ and consequently the phototoxicity of the BODIPYs. 13–15 On the other hand, halogenation at the 3,5-positions or at the BODIPY meso -phenyl or meso -thienyl substituents is not expected to significantly affect the cytotoxicity of the compounds.…”

“…Upon exposure to a low light dose (1.5 J/cm 2 ) all the β-free BODIPYs investigated showed low cytotoxicity (IC 50 >80 μM) in agreement with previous investigations. 15,48 Among the 2,6-diiodo-BODIPYs, 1a , 2a , 4a , 6a , 7a and 10a showed IC 50 values between 3.5 and 28 μM, while all others ( 3a , 5a , 8a , 9a and 11a ) showed IC 50 >200 μM. This is a surprising result, since the 2,6-diiodo-BODIPYs previously investigated are reported to have high phototoxicity, 14,15 attributed to the ‘heavy atom effect,’ and cleary shows the effect of the meso -aryl groups.…”

Functionalization of 3,5,8-Trichlorinated BODIPY Dyes

“…These methods include, but are not limited to, electrophilic and nucleophilic substitutions, palladium-catalyzed cross-couplings, aromatic ring fusion, and Knoevenagel condensations. 5−7 Among these, aromatic ring fusion 7,11,12 and cross-coupling reactions 13−16 are particularly useful for inducing bathochromic shifts of the BODIPY optical transitions via extension of π-conjugation, while substitution reactions 17−21 are often used to modify the molecular amphiphilicity upon introduction of heteroatom-based groups, and for bioconjugations. Halogenated BODIPYs are particularly versatile substrates for functionalization purposes via both cross-coupling and nucleophilic substitution reactions, and all halogens (fluoride, chloride, bromide, and iodide) have been introduced into the pyrrolic positions of BODIPY (or a dipyrromethane or pyrrole precursor), mainly using electrophilic substitution.…”

New Trends in Near-Infrared Fluorophores for Bioimaging

“…58 Much work has been published on the basis of this concept over the past years (e.g. benzo-fused BODIPY (112 -164), [59][60][61][62][63][64] benzo-fused B,O-chelated BODIPY (165 -167), 65,66 benzo-fused aza-BODIPY (168 -177), 37,67,68 and areno-fused BODIPY (178 -186) 69,70 ), and the following briefly describes the tendency of the effect of modifying the optical properties: about a 50 nm red shift is achieved by introducing one benzene ring, resulting in similar, or a bit lower, optical properties compared to that of the original BODIPY (spectral sharpness, extinction coefficients, quantum yields). The extinction coefficients are for the most part almost identical to, or lower than, those of BODIPY (~80000 M -1 cm -1…”