Meso-Substitution Controlled Synthesis of BODIPY–DPM Conjugates: A Pathway to Tailored Photophysical Properties

We show that the electronic nature of the meso-aryl substituent in 1,3,5,7-tetramethyl BODIPYs governs the reactivity of the 1,7-methyl (α-methyl) groups toward the Knoevenagel condensation. Reaction of pyrrole-2-aldehyde with electron-deficient 1,3,5,7-tetramethyl-meso-pentafluorophenyl and 1,3,5,7-tetramethyl-meso-4-nitrophenyl BODIPYs yields double condensation at the 1,7-methyl positions to give the corresponding bis(pyrrole) derivatives, whereas the electron-rich meso-tolyl analogue selectively undergoes single condensation at only one of the α-methyl groups under identical conditions. This substituent-dependent divergence extends to reactions with 1,9-diformyl-meso-aryl dipyrromethanes, enabling access to structurally distinct BODIPY–DPM conjugates. Reaction of 1,9-diformyl-DPM with meso-tolyl BODIPY selectively yields acyclic monosubstituted BODIPY–DPM conjugates, whereas the higher reactivity of meso-pentafluorophenyl BODIPY enables condensation between both 1,7-methyl groups and the two aldehyde functionalities of the diformyl-DPM scaffold, affording cyclic, porphyrin-like BODIPY–DPM frameworks. Notably, meso-pentafluorophenyl BODIPYs also undergo nucleophilic aromatic substitution of the para-fluorine atom by piperidine under the condensation conditions, as confirmed unambiguously by single-crystal X-ray diffraction. The resulting BODIPY–DPM and BODIPY–pyrrole conjugates exhibit pronounced bathochromic shifts (90–180 nm relative to parent BODIPYs), deep-red to near-infrared absorption (~670 nm) and emission (~750 nm), enlarged Stokes shifts, and strong intramolecular charge-transfer character. These features translate into efficient heavy-atom-free triplet formation, with singlet-oxygen quantum yields reaching up to 0.45. A representative conjugate (10) exhibits potent photodynamic activity in B16F10 melanoma cells with minimal dark toxicity (IC₅₀ = 0.95 μM). TD-DFT analysis indicates that excited-state twisting reduces ΔEST, thereby facilitating heavy-atom-independent intersystem crossing. Collectively, these results establish a robust molecular design framework for next-generation heavy-atom-free photosensitizers.