Theoretical insights into the rational design of small organic phototheranostic agents for promoting image-guided cancer surgery

Abstract

To realize the precise regulation of phototheranostics for AIE luminogens (AIEgens), unraveling the molecular configuration, molecular packing and phototheranostic property relationships is of vital importance. Through a multiscale modeling protocol that combines molecular dynamics simulations, implicit polarizable continuum models and thermal vibration correlation function formalism coupled quantum mechanics/molecular mechanics models, the inherent mechanism of two structurally similar donor–(π)–acceptor-type AIEgens (TI and TSSI) with significantly different performances in phototheranostics were firstly explored. It is found that TSSI with additional thiophene rings as a bridge largely improves the phototheranostic properties, which includes a redshifted emission, a high photothermal conversion efficiency (PCE) and a good intersystem crossing (ISC) efficiency. Based on that, we propose a molecular design strategy and design a series of AIEgens via structural modification of the acceptor moiety or extending the π-bridge of TSSI. It is found that, TSSSSI is predicted to be a potential candidate for NIR-II fluorescence imaging guided photodynamic and photothermal therapy applications owing to its excellent fluorescence efficiency, efficient ISC process, and emission spectrum in the NIR-II region. Lastly, the fluorescence quantum efficiency enhancement of TSSI upon aggregation was caused by suppressing the rotational vibrations in the low-frequency region. Our theoretical protocol is general and applicable to other AIEgens, thus laying a solid foundation for the rational design of advanced AIEgens for applications in phototheranostics.

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Introduction

Phototheranostic strategies using organic luminescence are experiencing a rapid development, because of their high accuracy, high efficiency and non-invasive nature,^1–5 which overcome the disadvantages of conventional tumor treatment methods with a high surgical risk and limited efficacy.^6,7 In current diagnostic technology, fluorescence imaging (FLI) has a high sensitivity, a fast response and is non-invasive, although it is limited in its penetration depth.^8,9 By contrast, photoacoustic imaging (PAI) has a centimeter-scale imaging depth, but lacks sensitivity.^10,11 Photothermal imaging (PTI) shows good temperature sensitivity and a real-time monitoring ability.^12,13 Photothermal therapy (PTT) and photodynamic therapy (PDT) are both light-controllable and non-invasive, but have heat shock effects and hypoxic nature, respectively.^14,15 The combination of different diagnostic and therapeutic techniques can overcome these intrinsic shortcomings and achieve both accurate diagnosis and a good treatment efficiency.¹⁶ In addition, the absorption and emission of long wavelengths in near-infrared (NIR) region are important in photo-theranostic applications in vivo, because they help to achieve better penetration into tissue with less damage¹⁷ and a high signal-to-noise ratio.^18,19

The performance of phototheranostics is closely related to the relative contributions of the different decay channels of photoexcited molecules. According to the Jablonski diagram, there are three key dissipative channels of excited state energies. First is the radiative channel, which generates fluorescence and affords FLI.^20,21 The second is the internal conversion process through thermal vibrations, which is utilized in PTI, PAI and PTT.¹⁴ The third is the intersystem crossing (ISC) process, which produces reactive oxygen species (ROS) for PDT.^22–24 The three decay channels of excited states compete with each other, and the energy partition between these different decay channels influences the probabilities of the different functions for phototheranostics. AIE luminogens (AIEgens) are ideal candidates for phototheranostics. AIEgens with non-planar twisted conformations pack loosely in the condensed phase, which is not only beneficial for fluorescent emission but also keeps the intramolecular motions active in the aggregates, and this could well balance the energy partition of the different decay channels of the excited states.^{3,12,13,19,25–30} The precise control of the energy partition on the different decay channels of AIEgens is key to regulating their performance in phototheranostics.

Nonetheless, the development of AIEgen-based organic luminescence for phototheranostics requires the optimization of many factors, such as the absorption/emission wavelength, the photothermal conversion efficiency, spin–orbit coupling (SOC), chemical stability and so on. These factors interplay with each other and cannot be optimized separately; therefore, it is a great challenge for researchers to design organic AIEgens through trial-and-error. Unraveling the microscopic mechanisms behind the phototheranostics of organic luminescence is a key prerequisite for the precise design of organic luminescence with good performance for phototheranostics; these remain elusive, however, due to the limited spatial-temporal resolution of current experimental techniques. Multiscale modeling has played an important role in elucidating the relationship between the molecular configuration, molecular packing and phototheranostic properties of AIEgens and understanding their system-dependent performance in phototheranostics, which is beneficial for the rational design of AIEgens at minimal cost compared with the trial-and-error screening approach of experiments.^31–35 This can be exemplified by two representative AIEgens: TI and TSSI. As shown in Scheme 1, TI consists of triphenylamine as the donor (D) and the 1,3-bis(dicyanomethylidene) indane moiety as the acceptor (A); for TSSI, except for the same D and A, it also comprises two additional thiophene rings as a π-bridge. Therefore, TI and TSSI are D–A and D–π–A type molecules, respectively, and their only difference is that TSSI contains the additional thiophene rings as the π-bridge. Although TI and TSSI have similar chemical structures, they display distinct performances in phototheranostics. Experimentally, TI and TSSI are both AIEgens, where TSSI displays much redder absorption (NIR-I) and emission (NIR-II) spectra than TI. In addition, TSSI simultaneously demonstrates a higher PCE and a superior ROS production efficiency than TI.³⁶ In contrast to TI, TSSI shows an unprecedented performance in NIR-II FLI-PAI–PTI trimodal-imaging-guided PDT–PTT synergistic therapy.³⁶

Scheme 1 Chemical structures of (a) TI and (b) TSSI. The acceptor, π-bridge, and donor are labeled in blue, orange and green, respectively, and the corresponding dihedral angles are A_n=1–5, B_n=1,2, and D_n=1–3, respectively.

In this contribution, we adopt a theoretical protocol that combines molecular dynamics simulations (MD), implicit polarizable continuum models (PCM) and hybrid quantum mechanics/molecular mechanics (QM/MM) models (see Fig. S1, ESI†)^37,38 to systematically explore the striking difference in the phototheranostic performance of TI and TSSI, which have similar chemical structures, at the microscopic level. Based on these theoretical calculations, we further design a series of AIEgens and study their potential abilities in phototheranostics to systematically optimize the performance of the AIEgens with respect to the target function of phototheranostics, such as NIR-II FLI. Finally, the AIE mechanism of the representative AIEgen TSSI is demonstrated.

Results and discussion

Phototheranostic properties of TI and TSSI

The structural changes in both TI and TSSI upon excitation were demonstrated. For clarity, the key dihedral angles of the acceptor, the π-bridge and the donor are defined as A_n (A₁, A₂, A₃, A₄, and A₅), B_n (B₁ and B₂) and D_n (D₁, D₂, and D₃), respectively (see Scheme 1). Moreover, the changes of the TI and TSSI bond lengths (within 0.03 Å) and bond angles (within 1.1°) are negligible (see more details in Table S2, ESI†). This indicates that TSSI is more flexible and displays more obvious structural modifications than TI in dilute solution. For example, the change in A₂ for TSSI (28.3°) is much larger than that for TI (3.3°) (see Fig. 1a and Table S2, ESI†). Upon excitation, the A backbone of TI becomes more planar and that of D is more twisted, as reflected by the decreased dihedral angles of the A moiety (A₁, A₂, A₃, A₄ and A₅) and the increased dihedral angles of the D moiety (D₁, D₂ and D₃). By comparison, the configuration of TSSI becomes more planar after excitation, because all the extracted dihedral angles of D, π-bridge and A are decreased, indicating that the introduction of the π-bridge effectively improves the conjugation of TSSI (Fig. 1b, c and Table S2, ESI†). The statistical population of the key dihedral angles of TSSI obtained from MD simulations also shows wider distributions than that of TI (Fig. 1d). For example, the distribution of D₁ in TSSI is in range of −180° to 180°, while that of TI is only in range of 10° to 180°; at the same time, B₁ and B₂ of the additional thiophene rings in TSSI also have a certain range of distributions (Fig. 1d). This indicates that the dynamic conformational changes of TSSI in aqueous solution are much easier than in TI (see the representative conformations of TI and TSSI in Fig. S2, ESI†). Therefore, TSSI is more flexible than TI, and it may release more heat energy vibrationally through the non-radiative decay channel of the excited state, which is beneficial for improving the performance in PTI, PAI and PTT.

Fig. 1 (a) Modification of dihedral angles between S₀ and S₁ of optimized TI and TSSI in dilute solution. (b and c) Selected dihedral angles of TI and TSSI at both S₀ and S₁. (d) Distributions of the representative dihedral angles of TI and TSSI based on MD trajectories. (e) HOMO, LUMO and energy gaps (ΔE_g), as well as (f) the orbital delocalization index of the HOMO and LUMO for the S₁-geometry of TI and TSSI in dilute solution. (g) Calculated absorption and emission spectra, as well as (h and i) the ΔE_ST and spin–orbit couplings (ξ) of TI and TSSI in solution.

The S₁ transition orbitals of TI and TSSI are both mainly contributed by HOMO → LUMO, although HOMO−1 → LUMO plays a minor role (Fig. 1e, Fig S3 and Table S3, ESI†). As shown in Fig. 1e, TI has a twisted intramolecular charge transfer (TICT) feature with the HOMO and LUMO distributed on the D and A moieties, respectively. TSSI shows a hybrid local excited (LE) and charge transfer (CT) state, with the HOMO and LUMO delocalized over almost the entire TSSI skeleton, because the introduced π-bridge largely improves the backbone planarity and enlarges the effective conjugation length for the S₁ of TSSI. Accordingly, the ΔE_g of TSSI (2.54 eV) is smaller than that of TI (2.86 eV) (see Fig. 1e). The orbital delocalization can be quantitatively characterized via the orbital delocalization index (ODI), where the smaller the ODI, the larger the extent of orbital delocalization. Clearly, the ODI of both the HOMO and LUMO of TSSI are smaller than those of TI, which is supportive of the increased planarity and conjugation of TSSI induced by the π-bridge (Fig. 1f). The absorption and emission spectra of TSSI are both redshifted compared with TI, because of the better planarity and the smaller ΔE_g of TSSI (Fig. 1g), in good agreement with the experimental results.³⁶ In particular, the absorption and emission spectra of TSSI fall in the NIR-I and NIR-II regions with peak maxima at 628 nm and 850 nm, respectively, which is also beneficial for its FLI application in vivo.³⁶

The ISC process is estimated from the energy gap (ΔE_ST) between S₁ and the low-lying triplet states (T₁ or T₂), as well as the SOC (ξ) values. Generally, reducing ΔE_ST or increasing ξ can effectively increase the ISC efficiency and enhance the PDT performance. As shown in Fig. 1h and i, the negligible ΔE_ST (0.001 eV) and the excellent ξ (0.45 cm⁻¹) between S₁ and T₂ for TSSI can realize a more efficient ISC process than TI, which shows ΔE_ST (0.136 eV) and ξ (0.63 cm⁻¹). Therefore, TSSI has a better performance in PDT applications than TI, consistent with experimental results.³⁶

Above all, in contrast to TI, the introduction of the thiophene-ring bridge between the donor and acceptor of TSSI largely improves its performance of the phototheranostic properties, which not only redshifts the absorption and emission spectra but also improves the PCE due to the boosting of non-radiative decay pathways. In addition, the small ΔE_ST and the large ξ value also enhance the PDT function. Therefore, TSSI has a better phototheranostic performance than TI, in good agreement with experimental results.³⁶

Molecular design

Further molecular design based on TSSI was performed to deepen our understanding of the structure–property relationship of the AIEgens on the phototheranostic performance. Two molecular design strategies were proposed to optimize the specific functions of the phototheranostics. (i) We introduced an additional electron-deficient cyano group at 4-position or 5-position of the indane moiety of TSSI, which are designated as o-TSSI or m-TSSI, respectively (see Fig. 2). Introducing a cyano group into the A moiety of TSSI only not can increase the electron-withdrawing ability of the A moiety and enhance the separation of D and A but also incorporates the steric hindrance of the cyano group into the molecular conformations and phototheranostic properties. (ii) We extended the π-bridge of TSSI to three or four thiophene rings, designated as TSSSI or TSSSSI, respectively, to further improve the conjugation length and red-shift the absorption and emission spectra of TSSI (see Fig. 2).

Fig. 2 Schematic illustration of the design strategies of the four organic molecules based on TSSI: o-TSSI, m-TSSI, TSSSI, and TSSSSI.

As shown in Fig. 3a and Scheme S2 (ESI†), the key dihedral angles of the A moiety (particularly for A₁ and A₂) of o-TSSI for both S₀ and S₁ are much larger than those of the other four AIEgens, TSSI, m-TSSI, TSSSI and TSSSSI, because of the steric hindrance of the 4-position of the indane moiety of o-TSSI. For example, A₁ increases from 12.2° and 1.2° for TSSI to 30.5° and 28.4° for o-TSSI for S₀ and S₁, respectively (Tables S2 and S4, ESI†). Therefore, the introduction of the additional cyano group at the 4-position of o-TSSI increases the steric effect of the A moiety and results in a more distorted conformation for o-TSSI (Fig. S4, ESI†). By contrast, for m-TSSI, the dihedral angles of the D, π-bridge and A moieties are all similar to those of TSSI, indicating the neglectable steric hindrance from introducing the cyano group at the 5-position of the indane moiety (Fig. S4 and Tables S2, S4, ESI†). Lengthening the π-bridge to three and four thiophene rings can enhance the planarity of the π-bridge (supportive of the small B₃ and B₄ in Fig. 3a, Fig. S4 and Table S4, ESI†) and enlarge the conjugation length of TSSSI and TSSSSI; therefore, the absorption and emission spectra of TSSSI and TSSSSI are more redshifted than TSSI.

Fig. 3 Structural and photophysical parameters of TSSI and four designed AIEgens: o-TSSI, m-TSSI, TSSSI and TSSSSI. (a) Selected dihedral angles for S₀ and S₁. (b) HOMO, LUMO and ΔE_g of the S₁ geometry. (c) Absorption and emission spectra. (d) Radiative rate constant (k_r) and total reorganization energy (λ_total) values. (e) Calculated ΔE_ST and spin–orbit coupling (ξ) values.

Similar to TSSI, all four designed AIEgens display hybrid LE and CT features, and the transition orbitals for S₁ are dominated by the HOMO → LUMO transition, with the HOMO mainly distributed on the D and π-bridge, and the LUMO distributed on the A and π-bridge, respectively (see Fig. S5 and Table S5, ESI†). For o-TSSI and m-TSSI, the introduced cyano group effectively increases the electron-withdrawing ability of the A moiety and enhances the degree of separation between the hole and the electron (see Fig. S6, ESI†); therefore, the ΔE_g values of o-TSSI and m-TSSI (2.52 eV and 2.47 eV) are smaller than that of TSSI (2.54 eV). In addition, the ΔE_g values of TSSSI and TSSSSI are decreased to 2.34 eV and 2.23 eV because of the increased conjugation length and planarity after lengthening the π-bridge of TSSI (Fig. 3a and b). Therefore, relative to TSSI, all the absorption and emission spectra of m-TSSI, TSSSI, and TSSSSI are redshifted with maximum emission wavelengths of 861 nm, 893 nm and 918 nm, respectively (Fig. 3c). It is clear that the absorption and emission spectra of TSSSSI cover almost the whole NIR-I and NIR-II regions. It is noted that the fluorescent emission of o-TSSI is blueshifted because of the torsional conformations induced by the steric hindrance of the additional cyano group at the 4-position of the indane moiety. Therefore, the strategy of lengthening the π-bridge is more conducive to the spectral redshift and is more effective for improving the FLI performance for phototheranostics in vivo.

The fluorescence quantum efficiency (Φ_F) is determined via the radiative decay rate (k_r) and the internal conversion rate constant (k_ic). The k_r value is calculated using the simple spontaneous emission relationship, whereas k_ic can be characterized via the reorganization energy (λ), and these are useful parameters for measuring the extent of electron–vibration coupling. In general, the increase in λ implies a larger k_ic. As shown in Fig. 3d and Table S5 (ESI†), the k_r values of the four designed compounds all increase from 0.6 × 10⁸ s⁻¹ (TSSI) to 1.5 × 10⁸ s⁻¹ (o-TSSI), 0.8 × 10⁸ s⁻¹ (m-TSSI), 0.9 × 10⁸ s⁻¹ (TSSSI), and 1.2 × 10⁸ s⁻¹ (TSSSSI), respectively; simultaneously, λ_total is reduced from 1.2 eV (TSSI) to 0.4 eV (o-TSSI), 1.0 eV (m-TSSI), 1.0 eV (TSSSI), and 0.8 eV (TSSSSI). In particular, o-TSSI with the cyano group at the 4-position of the indane moiety has the largest k_r and the smallest λ_total; therefore, this additional cyano group can effectively restrict the intramolecular vibrations of o-TSSI and improve its fluorescent emission. In addition, TSSSSI, with longest π-bridge, displays a larger k_r and a smaller λ_total than those of TSSI, and shows better FLI than TSSI. Therefore, both o-TSSI via the introduction of the additional cyano group at the indane 4-position and TSSSSI with the lengthened bridge dimension are beneficial for FLI.

Then, ΔE_ST and ξ were calculated to qualitatively estimate the ISC process (Fig. 3e). It is found that, ΔE_T2–S1 is reduced successively from o-TSSI (0.100 eV) to TSSSI (0.012 eV), m-TSSI (0.005 eV), TSSI (0.001 eV) and TSSSSI (∼0 eV), and the ΔE_T2–S1 value of TSSSSI is the smallest at almost equal to zero. Simultaneously, the corresponding ξ_T2–S1 values of all the compounds are of the same order of magnitude (0.19 cm⁻¹, 0.29 cm⁻¹, 0.26 cm⁻¹ 0.45 cm⁻¹ and 0.15 cm⁻¹), indicating the relative facilitated ISC process and the good performance for PDT (Fig. 3e). Therefore, the TSSSSI with the π-bridge lengthened to four thiophene rings is predicted to be a potential candidate for phototheranostic applications owing to its excellent FLI, efficient ISC process, and emission spectrum in the NIR-II region.

Aggregation effect

The hybrid QM/MM models of representative amorphous aggregates were set up to elucidate the aggregation effects of TSSI and to systematically investigate the influence of the molecular packing on the photophysical properties of TSSI. Considering the irregular molecular packing of TSSI in amorphous aggregates, three representative conformations were randomly selected and the QM/MM models set up accordingly to calculate their photophysical properties (Fig. 4a). It was found that the TSSI monomer is more flexible compared with as amorphous aggregates, due to the dense molecular packing, and the structural modifications upon excitation are sharply decreased after aggregation (Fig. 4b and Tables S2, S6, ESI†). For example, the structural modification of A₂ and A₅ of TSSI are largely reduced from 28.3° and 32.2° in the dispersed state to 4.4° and 4.9° in an amorphous aggregate, respectively. Moreover, the backbone of TSSI suffers a significant distortion from linear to bent upon aggregation, which is supported by the variation of B₁ and B₂ from 7.1° and 0.2° in the dispersed state to 18.8° and 37.8° in an amorphous aggregate for the S₁-geometry (Fig. S7, ESI†).

Fig. 4 (a) QM/MM model of TSSI as an amorphous aggregate, where one central TSSI was selected as the QM region and the others were set as the MM region. (b) Structural modification between S₀ and S₁, as well as (c) the HOMO, LUMO and energy gap (ΔE_g) for the S₁-geometry of TSSI in monomer and amorphous aggregate forms. (d) Calculated absorption and emission spectra of TSSI in monomer and amorphous aggregate forms. (e and f) Projection of the reorganization energy in the ground state (λ_gs) on the normal mode frequency and internal coordinates of TSSI in monomer and amorphous aggregate forms.

The major transition orbitals, HOMO and LUMO, of TSSI are localized at the D and A moieties, respectively (Fig. 4c, Fig. S8, and Table S7, ESI†), showing the ICT features. Due to the twisted backbone and the reduced conjugation after aggregation, the corresponding ΔE_g of TSSI in the aggregate (2.62 eV) is larger than that of the dispersed form (2.54 eV), and therefore the emission spectrum of TSSI is blueshifted upon aggregation (Fig. 4c, d and Fig. S9–S11, ESI†). Moreover, the absorption and emission spectra of TSSI in the amorphous aggregate fall in NIR-I and NIR-II regions with peaks at 706 nm and 824 nm, respectively. Relative to TSSI in the dispersed state, the emission spectrum of the amorphous aggregate is blueshifted.

The k_r, k_ic and Φ_F data of TSSI in the amorphous aggregate were also estimated using the thermal vibration correlation function protocol through the MOMAP program.^39–41 The calculated k_r and k_ic values of TSSI in the amorphous aggregate are 2.9 × 10⁷ s⁻¹ and 6.6 × 10⁶ s⁻¹, respectively, and the corresponding Φ_F is 81.5% (Table S7, ESI†). As reported in previous studies,^32,42–45k_r is immune to the environment, and the k_r of TSSI in solution and the amorphous aggregate are of the same order of magnitude. By contrast, k_ic is quite sensitive to the environment and is closely related to λ. It was found that the λ_total of TSSI in dilute solution is 1.2 eV, whereas it decreases to 0.4 eV in the aggregated state (Table S7, ESI†), implying the much larger k_ic of TSSI in solution compared with that as an amorphous aggregate; therefore, the Φ_F of TSSI in the aggregate is improved upon aggregation. To gain more theoretical insights into the suppressed non-radiative channel in the aggregated state, we further projected the λ_gs values of TSSI in both solution and the aggregated state for S₀ into the vibrational normal modes (Fig. 4e). It can be seen that the λ_gs values of TSSI are much smaller as aggregates than in dilute solution, particularly for the low-frequency region (<300 cm⁻¹) (see Fig. 4e). Moreover, the summation of λ_gs for TSSI in the low-frequency region in solution and in the aggregated form is 411 meV and 97 meV, respectively. These findings indicate that the energy dissipation pathways are easily blocked via low-frequency components upon aggregation. To clarify the relationship between the energy dissipative channel and the molecular structure, we projected the λ_gs of TSSI in both the solution and aggregated form onto the internal coordinates (Fig. 4f). It is noted that the contribution from the dihedral angles decreases from 496 meV in solution to 70 meV in the aggregated state, while the changes for the bond length and bond angle are negligible (Fig. 4f). The major components of the dihedral angles are associated with the out-of-plane motions of the A moieties, consistent with analysis of the structural modifications in Fig. 4b. These results confirm the crucial role of the phenyl-ring motions of the A-moiety in determining the photophysical properties of TSSI, which is fully consistent with the structural modification from S₀ to S₁ (Fig. 4b).

Conclusions

In summary, the underlying mechanisms of the dramatically different phototheranostic performance characteristics of two structurally similar AIEgens (i.e., TI and TSSI) were first explored using a multiscale modeling protocol that combines MD simulations and the PCM model. It is found that TSSI, which contains a thiophene-ring bridge to link the donor and acceptor moieties, shows largely improved phototheranostic properties that include a redshifted emission, a higher PCE and a good ISC efficiency. Therefore, TSSI has a better phototheranostic performance for PTI, PTT, PAI, and PDT compared with TI, which is consistent with experimental results.³⁶ Based on unraveling the structure–property relationship of TSSI, we propose a rational molecular design strategy, and further design a series of AIEgens via structural modification of the A moiety or by extending the π-bridge of TSSI. It is found that, relative to structural modification of the A moiety of TSSI, the lengthening of the π-bridge, particularly for TSSSSI, is predicted to provide a potential candidate for phototheranostic application owing to its excellent FLI, efficient ISC process, and emission spectrum in the NIR-II region. Lastly, the aggregation effects of the representative AIEgen TSSI were explored using a multiscale modelling protocol that combines MD simulations and the thermal vibration correlation function formalism coupled QM/MM model. It is demonstrated that the enhancement of the fluorescent quantum efficiency of representative TSSI was realized by blocking the excited-state non-radiative decay channels through suppressing the rotational vibrations in the low-frequency region. These calculations demonstrate a clear picture of the relationship between the molecular configuration, the molecular packing and the phototheranostic properties, which could provide valuable insight for the rational design of high-performance AIEgens for phototheranostics.

Conflicts of interest

The authors declare that they have no conflict of interest.

Acknowledgements

We thank the financially supporting of the Beijing Natural Science Foundation (Grant 2222027), the National Natural Science Foundation of China (Grants 22173006) and the Open Fund of Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates (South China University of Technology, 2019B030301003), as well as the General Project of Chinese Academic Degrees and Graduate Education Society, grant number: 2020MSA431.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2qm01227h

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