# Recent Development of Heavy Atom-Free Triplet Photosensitizers for Photodynamic Therapy
## 3 Twisted \(\pi\)-Conjugation Framework-Induced ISC
With the ZFS parameter \(D\) value, we predicted the distance between the radical and the chromophore, which was in agreement with the single crystal X-ray diffraction analysis and the DFT optimizations. We used the radical-based triplet PSs for TTA upconversion, and the quantum yield was 6.7% [112]. Later we used this strategy to prepare the radical-Bodipy triad (Figure 17) [113]. Our expected molecular structure is **52**, based on the previously reported amino substitution at the _meso_-position of Bodipy (with the _meso_-chloromethyl Bodipy as the starting material). However, carefully \({}^{1}\)H NMR analysis and single-crystal X-ray diffraction show the molecular structure was actually **53** (Figure 17). Thus, an unexpected nucleophilic substitution occurred on the methyl groups at 3- (or 5-) position of Bodipy (which is without any chloro substitution) [113]. Figure 16: TEMPO-Bodipy dyads as radical-chromophore heavy atom-free triplet PSs. Figure 15: Simplified energy diagrams showing (**a**) the electron spin forbidden ISC in organic chromophore and (**b**) the electron spin allowed ISC of the chromophore in a chromophore-radical three electron spin system. Reproduced with permission from reference [101], copyright 2001, American Chemical Society. (**c**) Molecular structures of some typical radical-chromophore triplet PSs. UV-Vis absorption spectra showed a strong interaction between the two Bodipy units in the triad **53** at the ground state, indicated by the splitting of the absorption band, but the splitting character was different from that resulting from exciton coupling and H-/J-aggregation. The fluorescence of the Bodipy unit in **53** was significantly quenched, and \(\Phi_{\Delta}\) was up to 59%. Interestingly, the triplet-state lifetime was determined as 2.8 us, much shorter than that of **54** (27 us). Similarly, nitronyl nitroxide radical-induced ISC was also observed in oligothiophenes [114]. The above TEMPO-Bodipy compounds absorb green light. Amino-substituted NDI was used to prepare radical-based heavy atom-free triplet PS showing red light absorption (Figure 18. \(\varepsilon\) = 20000 M\({}^{-1}\) cm\({}^{-1}\) at 606 nm) [115]. Different from the analogue-without-radical unit, i.e., **56** (\(\Phi_{\text{F}}\) = 24%), the \(\Phi_{\text{F}}\) is decreased for **55** (\(\Phi_{\text{F}}\) = 3%). Interestingly, the \(\Phi_{\Delta}\) of **55** is significantly increased (\(\Phi_{\Delta}\) = 50%) as compared to the reference compound **56** (\(\Phi_{\Delta}\) = 2%). Fs-TA spectra indicate the radical-enhanced ISC took 338 ps. The triplet-state lifetime of the **55** was 8.7 us, much shorter than **56** (\(\tau_{\text{T}}\) = 242 us). Liposomes prepared from NDI-TEMPO showed strong PDT effect (phototoxicity EC\({}_{50}\) = 3.22 uM) [115]. A similar strategy was used by [PERSON] et al. to prepare radical containing triplet PSs by attaching TEMPO to the _meso_-position of a Cy7 dye (**57**, Figure 19) [116], which absorbs at 660 nm. The triplet-state lifetime of the **57** was determined as 9.16 us, and the \(\Phi_{\Delta}\) is 20%. The dyad showed a desired low dark cytotoxicity (IC\({}_{50}\) = 715.4 uM), and the light toxicity was IC\({}_{50}\) = 14.2 uM. These results showed that the radical-chromophore dyads triplet PSs could become a new kind of PDT reagents. Figure 17: TEMPO-Bodipy triad **53** prepared based on an unexpected nucleophilic substitution reaction of Bodipy. **54** is a reference compound. Triad **52** is the anticipated product, base on the previously reported Bodipy derivatization chemistry. However, it was not obtained in our synthesis. Figure 18: NDI-TEMPO dyad **55** as red light-absorbing triplet PS and the reference compound **56**.