title: 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.
authors.affiliation: Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Timsy
authors.initials: T
authors.lastname: Uppal
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Hu
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.forename: Stephanie
authors.initials: S
authors.lastname: Maschek
authors.forename: Petia
authors.initials: P
authors.lastname: Bobadova-Parvanova
authors.forename: M Graça H
authors.initials: MG
authors.lastname: Vicente
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D018360:Crystallography, X-Ray; D003603:Cytotoxins / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D010084:Oxidation-Reduction
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D003603:Cytotoxins; D005456:Fluorescent Dyes