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-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 p-extended BODIPYs show strong red-shifted absorptions and emissions, about 5060 nm per benzoannulated ring, at 589658 and 596680 nm, respectively. In particular, db-BODIPY 4?c bearing a meso-C6F5 group showed the longest ?max 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.