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

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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-C6F5 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 6F5 group showed the longest λmax of absorption and emission, along with the lowest fluorescence quantum yield (0.31 in CH2Cl2); 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. Two synthetic routes to benzo- BODIPYs from a pyrrolic precursor were investigated. Computational calculations showed similar relative energies for all reaction intermediates and products in both routes. X-ray analyses indicated that benzannulation enhances the planarity of the BODIPY core (see figure). The benzo-BODIPYs show red-shifted absorptions and emissions, ca. 50-60 nm per benzoannulated ring, and high fluorescence quantum yields. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Chemistry - A European Journal

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