English

• The standard treatments for cancer often come with significant side effects and risks, particularly from surgical procedures, and they typically show limited effectiveness against large tumors [1,2]. As a result, photodynamic therapy (PDT) has recently emerged as a promising alternative for cancer treatment, attracting increased attention [3–6]. PDT operates on the principle of administering a photosensitizing agent, either intravenously or topically, followed by irradiating the cancerous tissue with specific wavelengths of light. This initiates a photoexcitation process where the photosensitizer transitions from a ground state (S₀) to an excited singlet state (S_n). This is followed by intersystem crossing (ISC) to an excited triplet state (T_n), leading to reactions that produce reactive oxygen species (ROS) to destroy the tumor. Additionally, the transition back to the S₀ state involves fluorescence emission, suggesting a trade-off between ROS generation and fluorescence intensity in photosensitizers [7].

  A key challenge in developing photosensitizers is optimizing the balance between fluorescence quantum yield (Φ_f) and singlet oxygen quantum yield (Φ_Δ). Donor-acceptor (D-A) type photosensitizers [5,8–11] manage this by tuning the electron-donating and accepting properties of their components. In D-A systems without heavy atoms [12,13], the ISC often involves a charge transfer (CT) state, leading to the ¹CT → ³LE (locally excited) process [14,15]. In earlier research [16–19], the identification of charge transfer recombination in heavy atom-free D-A type distyryl-BODIPY photosensitizers was primarily established by altering solvent polarity and confirmed through femtosecond and nanosecond transient absorption spectroscopy. Unfortunately, the aforementioned studies do not provide a clear microscopic description of the charge transfer-recombination process from the ¹CT to the ³LE.

  To bridge the existing knowledge gaps regarding charge transfer-recombination in photosensitizers, our research centered on a systematic study of experimentally synthesized M1-M3 [18,19] in Scheme 1. These molecules display maximum absorption and emission in the near-infrared range when dissolved in toluene. M3, modified with a phenothiazine electron-donating group attached to distyryl-BODIPY, exhibits increased Φ_f and decreased Φ_Δ. In contrast, M2, which introduces a fluorine group at the para position of the benzene ring in M3, boasts enhanced electron-withdrawing capacity and significantly higher Φ_Δ. M1 with a benzene donor group, serves to contrast the electron-donating strength less robust than phenothiazine, underpinning the pivotal role of donor characteristics in modulating singlet oxygen production. Donors with multiple heteroatoms like oxygen, sulfur, and nitrogen demonstrate enhanced electron-donating capabilities [5,10,17–19]. We suggest that the lone-pair electron on these heteroatoms can integrate into the donor's π-conjugated system, boosting electron donation. Based on this, we designed molecules M5-M7 with donor groups containing both thiophene [20] and nitrogen rings [21]. Adjusting the sizes of the nitrogen rings, we modulated the donors' strain energy [22], fine-tuning their oxidation potentials and electron-donating properties, which is crucial for reducing the ΔE_ST and improving ISC efficiency. We also introduced a comparative molecule, M4, combining triphenylamine as the donor with distyryl-BODIPY as the acceptor [23–25]. This comparison will enhance our understanding of sulfur's role in modulating excited states. To further probe the ISC process in D-A type photosensitizers transitioning from ¹CT to ³LE, we applied computational chemistry (detailed in Supporting information) to analyze geometric configurations, oxidation potentials, strain energy, energy level diagrams, and electron-hole orbital interactions for molecules M1-M7.

  Scheme 1

  

  Scheme 1.  Chemical structure and photophysical properties of reported M1-M3 [18,19] and predicted M4-M7 in this work (acceptor in blue, donor in yellow).

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  To investigate the impact of conformation on the photophysical behavior of the seven molecules, we analyzed their major bond lengths, bond angles, and dihedral angles (Table S1 in Supporting information). In the S₀, S₁, and T₁ states, the dihedral angles between the donor and acceptor (C1-C2-C3-C4) for molecules M1 through M7, illustrated in Figs. S1-S7 (Supporting information), consistently measure around 90°. This consistency suggests minimal conformational variation in these states. However, a significant divergence is observed in the S₂ state, where molecules M2-M4 exhibit a twisted configuration, contrasting with the orthorhombic configuration of M5-M7. Subsequent computational analysis identifies the S₂ state as a charge-transfer state, highlighting the significant impact of conformation on photophysical properties. The orthorhombic configuration of M5-M7 in S₂ state enhances charge transfer efficiency relative to the twisted configuration of M2-M4. This discrepancy affects the π-conjugation, influencing molecular orbital angular momentum and necessitating adjustments in spin angular momentum to preserve total angular momentum conservation [26]. These adjustments are crucial as they support ISC, a key process for efficient transitions between singlet and triplet states and for enhancing singlet oxygen generation.

  To assess the impact of nitrogen-containing aliphatic rings on the electron-donating abilities of molecules M5-M7, we first calculated their strain energies using a homodesmotic reaction method [22], where higher strain energy indicates lower stability, with M5 being the least stable (Table S2 in Supporting information). Next, we evaluated their oxidation potentials with Eq. S2 (Supporting information). Data from Table S3 (in Supporting information) shows that higher oxidation potentials (E_OX) suggest weaker electron donation [27], following the order: M1 > M4 > M2 = M3 > M6 > M7 > M5. Combining the results from the strain energy and oxidation potential calculations, we deduce that M5 possesses the strongest electron-donating capability among molecules M5, M6, and M7.

  This suggests that a lower number of heteroatoms is associated with weaker electron donation. Molecules M5-M7, having lower oxidation potentials compared to M2 and M3, exhibit stronger electron-donating properties, attributed to their thiophene and nitrogen-containing aliphatic rings. Additionally, the near-vertical configuration of M5-M7 in the S₂ state works synergistically with the enhanced electron donation to promote charge separation in the CT states, facilitating ISC through the ¹CT → ³LE pathway. Thus, the observed consistency between strain energy and oxidation potentials confirms that precise control of strain energy is crucial for fine-tuning the ISC rate.

  To probe the absorption and emission behavior, we computed the absorption and emission wavelengths and frontier orbitals of molecules M1-M7 (Tables S4 and S5 in Supporting information). Discrepancies between calculated and experimental values are due to theoretical approximations, but trends are consistent with experimental data [28]. The molecular orbitals of M1-M7 (Fig. 1, Figs. S8-S10 in Supporting information) show that HOMO → LUMO and HOMO-1 → LUMO transitions correspond to S₀ → S₁ and S₀ → S₂ transitions, respectively, with oscillator strengths over 0.01, indicating allowed transitions. The significant HOMO-LUMO overlap suggests enhanced radiative decay from S₁ to S₀, potentially resulting in fluorescence emission from all M1-M7 [29]. M1 displays the highest oscillator strength (f = 1.1282) among the molecules. According to Eq. S3 (Supporting information), we calculated the radiation transition rate coefficients (fluorescence) k_r for seven molecules (Table S6 in Supporting information). Among M1-M3, M1 exhibits the highest radiative transition rate coefficient, aligning with its highest experimentally observed fluorescence quantum yield. M2-M7 show k_r values near 2.00 × 10⁸ s^-1, indicating their potential to emit fluorescence as visualizers.

  Figure 1

  

  Figure 1.  Frontier orbitals of the optimized S₀ state and the S₁ state geometries for M5.

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  In the hole-electron diagram, the electronic excitation characteristics are clearly depicted [30–32]. The D_he value, which measures the distance of the center-of-mass between the hole and the electron, and the t value (t is stated in more detail in Eqs. S4-S6 in Supporting information), which measures the degree of separation between the hole and the electron, are both critical parameters. Electron density difference plots are essential for analyzing the electron migration trajectory between two electronic states. As shown in Fig. S11 (Supporting information), the S₁ state of all molecules have small D_he value and negative t value, the holes and electrons are distributed on the acceptor moiety which indicates that the S₁ state of M1-M7 is a ¹LE state with no significant change in the distribution region before and after the electronic excitation. As seen in Fig. S12 (Supporting information), the S₂ state of M1 has both hole and electron delocalized domains throughout the molecule one can categorize the S₂ state as a ¹LE state which can also be judged by the small D_he value and the negative t value. We speculate that the inability of the M1 molecule to generate ¹O₂ (singlet oxygen) is primarily due to its failure to produce a ¹CT state and inefficient ISC.

  In our investigation of the electronic excitation characteristics of molecules M2, M3, and M5-M7, we observed that the distances between sulfur (S) atoms and acceptors significantly influence the electronic properties. Specifically, in the S₂ state, the S-BODIPY distances in M2 and M3 measure approximately 5.1 Å, whereas in M5-M7, these distances are substantially shorter, around 2.8 Å (Figs. S1-S7 in Supporting information). This reduction in distance in M5-M7 enhances electronic coupling, which likely facilitates more efficient charge transfer and supports the formation of CT excited states. This hypothesis is corroborated by the larger net charge transfer observed between donors and acceptors in M5-M7 compared to M2 and M3, as detailed in Table S7 (Supporting information). Further analysis of the electronic states of molecules M2-M7 revealed that in the S₂ state, a large D_he value and a positive t value (Fig. 2A and Figs. S13A-S17A in Supporting information) indicate that the holes are predominantly located on the donors and the electrons on the acceptors, classifying the S₂ state as a ¹CT state. Conversely, in the T₂ state, D_he values decrease and t values become significantly negative, suggesting that the T₂ state is a ³LE state with holes and electrons primarily located on the acceptor. Significant electron recombination from the S₂ to the T₂ state is evident in the electron density difference plots (Fig. 2B and Figs. S13B-S17B in Supporting information) of M2-M7, confirming a ¹CT → ³LE transition. This transition, involving charge transfer and recombination, could potentially enhance ISC. Notably, M5 exhibits the highest electron-donating capability among these molecules, which is accompanied by the greatest hole-electron separation, as reflected by its largest t value in the S₂ state and a maximum net charge transfer of 0.876 between donor and acceptor. M4 contains triphenylamine, which has a smaller oxidation potential than M1 which also reflected in the fact that the net charge transfer between its donor and acceptor is much larger than that of M1, indicating that it is a stronger electron donor than the benzene ring in M1 can induce larger D_he and positive t values in S₂ state. The donor oxidation potential of M4 is slightly higher than that of M2, M3, M5-M7, indicating a weaker electron-donating capacity than them, which is also reflected in the fact that the net charge transfer between donor and acceptor in S₂ state of M4 is slightly smaller than that of M2, M3, M5-M7, resulting in marginally smaller D_he and t than M2, M3, M5-M7. These minor variations are due to the absence of sulfur atoms in M4's donor, but they do not alter the fact that M4 exhibits similar electronic excitation characteristics to M2, M3, and M5-M7.

  Figure 2

  

  Figure 2.  (A) The hole (blue)-electron (yellow) diagram and (B) the electron density difference between the S₂ state and the T₂ state diagram of M5 (blue represents a decrease in electron density and yellow represents an increase in electron density).

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  To examine how the introduction of S atoms affects the excited states, we have analyzed the excitation types of S₂ and T₂ states of M2, M3, and M5-M7 in Table S8 (Supporting information) by natural transition orbital (NTOs). The results show that the excitation modes for both the S₂ and T₂ states of these five molecules are π → π^*. When enhancing the value of the occupied NTO isosurface for the S₂ state during rendering, the molecular NTO isosurface clearly retains its π-orbital characteristic. In this setup, the n-electrons from sulfur atoms participate in π-conjugation with the donors in both the S₂ and T₂ states, without leading to n → π^* excitation modes. To characterize that the addition of heteroatoms can expand the π-conjugation, we analyze the π-electron distribution of M1-M7 (Fig. S18 in Supporting information), where the green color represents the distribution of π-electrons, and it can be seen that there are π-electrons distributed on the heteroatoms. This facilitates electron transfer between donors and acceptors. In addition to this, S has a different hybridization pattern in thiophene and phenothiazine. The S atom in thiophene forms a conjugated system with the carbon atom through sp² hybridization, and its lone pair of electrons is highly delocalized from the π system of the entire five-membered ring. The structure of phenothiazine is more complex, with a bridging structure formed between the S and N atoms. We have analyzed the π-electron's net charges of the S atoms in M2, M3, and M5-M7 (Table S9 in Supporting information), and although the S atoms are still involved in the conjugated system of phenothiazines, the π-electron's net charges of the sulfur atom in M2 and M3 are lower than those of thiophene. These results reveal that the introduction of S can increase the degree of π-conjugation of the donor, and when S is involved in the formation of π-bonds in sp² hybridization, the π-electronic is distributed more on the S, which contributes to the further formation of CT states.

  To investigate the ISC process in compounds M1-M7, we constructed photophysical process diagrams. These diagrams integrate the vertical energies of the S₀, S₁, S₂, T₁, and T₂ states, SOC values, and ISC rate constants (k_isc in Table S10 in Supporting information). Based on the electronic excitation characteristics, we identified that the ISC channel for M2-M7 is primarily S₂ → T₂, driven by the transition from ¹CT to ³LE after excitation to S₂. Once in the T₂ state, the molecules undergo internal conversion to the T₁ state. Furthermore, for effective ISC, photosensitizer molecules should display smaller energy gaps between singlet and triplet states (ΔE_ST), larger SOC values to enhance the k_isc and a large energy gap between T₁ and S₀ to sensitize ³O₂ (triplet oxygen) to ¹O₂.

  For molecules M2, M3, M5, M6, and M7, the ΔE_S2-T2 are 0.577, 0.554, 0.193, 0.157, and 0.163 eV respectively, as shown in Figs. 3A and B. Their corresponding spin-orbit coupling (SOC) values are 0.39, 0.41, 0.74, 0.73, and 0.73 cm⁻¹. The intersystem crossing rates (k_isc) for M5-M7 are significantly higher than those for M2 and M3, indicating that enhanced donor capacity facilitates ISC. The attachment of an electron-withdrawing fluorine atom to M2′s receptor boosts its electron-accepting ability, leading to a more pronounced electron push-pull effect and a higher k_isc value compared to M3. This is consistent with M2′s higher experimentally measured quantum yield of singlet oxygen relative to M3. Overall, M5-M7 are predicted to exhibit stronger ISC capacity and potentially higher singlet oxygen production than M2 and M3. M1, with the largest ΔE_S2-T2 at 1.156 eV and the SOC value of 0.00 cm^-1 (Fig. 3A), cannot undergo ISC, making it suitable only as a fluorescent dye. M4 primarily undergoes ISC through the S₂ → T₂ channel, with an energy gap of 0.422 eV and an SOC value of 0.02 cm⁻¹ (Fig. S19 in Supporting information). The absence of sulfur in M4, as explained in Eqs. S7 and S8 (Supporting information), leads to lower SOC values and consequently a lower k_isc compared to other molecules with multiple heteroatoms, this variation in SOC values among these molecules can be attributed to the dependency of the SOC value on the atomic number, where a higher nuclear charge strengthens the effective magnetic field, thereby intensifying the spin-orbit coupling effect.

  Figure 3

  

  Figure 3.  (A) Energy level diagram of M1-M3. (B) Energy level diagram of M5-M7.

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  In this study, we examined the potential of D-A-type photosensitizers for dual-functional applications, specifically in fluorescence imaging and ¹O₂ generation. We focused on molecules M2-M7, which incorporate heteroatoms into the donor structure. This modification was found to decrease the oxidation potential and enhance the electron-donating ability, thereby facilitating efficient ISC. Additionally, the introduction of sulfur atoms into these molecules enhances the π conjugation of the donor, which not only provides more electrons but also strengthens the spin-orbit coupling. Electron density difference and hole-electron maps further confirm that ISC in M2-M7 is governed by the ¹CT → ³LE mechanism via the S₂ → T₂ transition. The effectiveness of these molecules in fluorescence imaging is supported by the high overlap between the HOMO and LUMO in the S₁ state and significant k_r, indicating robust fluorescence capabilities across all these molecules. As a result, these molecules are effective as both therapeutic agents and visualization tools. Whereas M1 is limited to imaging due to its inability to undergo ISC. Specifically, in molecules M5-M7, we fine-tuned the ISC process by adjusting the strain energy in nitrogen-containing aliphatic rings attached to the thiophene unit. These modifications resulted in lower oxidation potentials compared to M1-M4, suggesting a stronger electron-donating capacity. Consequently, M5-M7 exhibit smaller ΔE_S2-T2, larger SOC constants, and higher k_isc, will lead to more efficient triplet state formation and enhanced ¹O₂ generation, with M5 expected to be the most effective singlet oxygen generator. These findings provide valuable insights for designing dual-functional D-A-type photosensitizers tailored for therapeutic and imaging applications.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Jianfang Cao: Writing – review & editing, Visualization, Project administration, Methodology, Funding acquisition, Conceptualization. Xue Ma: Writing – original draft, Visualization, Validation, Methodology, Formal analysis, Data curation. Xinyu Chen: Visualization, Methodology. Tianci Zhang: Visualization, Methodology. Wen Sun: Writing – review & editing, Conceptualization.

  Acknowledgments

  This work was financially supported by the Fundamental Research Funds for the Central Universities (No. DUT20RC(3)076) and Natural Science Foundation of Liaoning Province (No. 2020-MS-293)

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.110897.

  
  
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• 

  Scheme 1  Chemical structure and photophysical properties of reported M1-M3 [18,19] and predicted M4-M7 in this work (acceptor in blue, donor in yellow).

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  Figure 1  Frontier orbitals of the optimized S₀ state and the S₁ state geometries for M5.

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  Figure 2  (A) The hole (blue)-electron (yellow) diagram and (B) the electron density difference between the S₂ state and the T₂ state diagram of M5 (blue represents a decrease in electron density and yellow represents an increase in electron density).

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  Figure 3  (A) Energy level diagram of M1-M3. (B) Energy level diagram of M5-M7.

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