Investigation of boron–fluorine bond reactivity in meso-aryl-substituted BODIPYs towards carborane O-nucleophiles

Introduction

BODIPYs, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes, are important compounds that have been intensively studied since their discovery by A. Treibs and F. H. Kreuzer in 1968 [1]. They have a number of valuable physicochemical properties, such as excellent chemical and photostability, high molar absorption coefficients, high fluorescence quantum yields, relatively small Stokes shifts, narrow absorption and emission peaks [2,3] which enable their use in a variety of applications [4-8]. Based on these excellent photophysical properties functionalized BODIPY systems have found applications in various fields, such as cell imaging [9], fluorescent probes [10], luminescent devices [11], organic light-emitting diodes (OLEDs), laser dyes [12], molecular switches [13], and non-linear optical materials [14]. These compounds are also actively used in biomedical applications as triplet photosensitizers [15], agents for photodynamic (PDT) and photothermal (PTT) antitumor therapies [16,17], agents for bioimaging and disease diagnostics [18] as well as sensors for monitoring a variety of biological processes [19]. An important factor determining the potential of using outstanding BODIPY characteristics is their chemical diversity since several strategies have been developed to introduce a variety of functional groups at different sites on the BODIPY core. The starting BODIPYs are readily prepared by reacting dipyrromethenes with boron trifluoride etherate [20] with the required dipyrromethenes accessible through condensation of either aldehydes with pyrroles and oxidation of the dipyrromethane intermediates or directly through condensation of acyl chlorides or anhydrides with pyrroles [20]. It has been shown that the introduction of substituents has a significant impact on the electronic and photophysical properties of BODIPY and methods have been developed to functionalize every position of the BODIPY core [21]. There are three main specific sites in the BODIPY skeleton: the meso-position (C8 carbon atom), the carbon atoms of the pyrrole fragments and the boron site whose modifications enable subtle tuning of the compounds’ physicochemical and biological properties, solubility, and reactivity affording a variety of derivatives with multiple advantages [22]. To increase the application potential of BODIPYs the modification of the meso-position could be important. Meso-substituents at the C8 site of BODIPY influence the photophysical, electrochemical, and structural properties exhibiting pronounced effects on fluorescence wavelengths, quantum yields, and Stokes shifts as well as biomedical applications [23]. Due to the wide variety of functional groups that can be attached to the C8 atom the introduction of a particular functionality at this position mainly depends on the intended area of application. Moreover, the free rotation of the meso-substituents in the BODIPY acts as a primary control for its optical and photophysical properties. Pyrrole units also play an important role in BODIPY structures defining their unique photophysical properties, such as optical stability, intense fluorescence, and high extinction coefficients as well as versatile sites for chemical modification [24]. In addition to functionalization of the BODIPY core at the meso- and pyrrole carbon sites, the substitution of fluorine atoms in the BF₂ unit was realized to give a wide range of new derivatives. The boron center of BODIPY provides free rotation of substituents as well as the ability to construct asymmetric dyes by introducing nucleophilic substituents at the boron atom through replacement of the boron-bound fluorine which can lead to an increase in fluorescence quantum yields and Stokes’ shift of the BODIPY fluorophore, improving chemical stability, and increasing water solubility [25]. There are reasons to assume that the same structure fragment can exert different properties in BODIPY according to its site of attachment [24,26]. Depending on the direction of BODIPYs applications, a search for new molecular structures is underway. Among the various BODIPY derivatives that have been studied over the years, conjugates with carborane polyhedra have demonstrated promising efficacy in improving the photophysical properties with influences on other conjugate characteristics such as cellular uptake in PDT [27] or in optoelectronic applications, including organic light-emitting diodes (OLEDs) and sensors [28]. The conjugation of icosahedral carborane clusters to the BODIPY core has been of great interest because of their special features such as remarkable chemical and thermal stability along with high hydrophobicity and lipophilicity, outstanding heat-oxidation and metabolic stability. Carboranes can be regarded as three-dimensional quasi-aromatic systems with a high level of delocalization of their skeleton electrons on a cage framework [29]. This unique physical property determines various functions of hybrid systems containing carborane clusters as substituents and carborane hybrid structures have found a broad range of applications in materials science, medicine, organic synthesis, and other areas [30-32]. Over the years, carborane compounds have been intensively studied as fluorophores [33], enzyme inhibitors [34], and potential agents for boron neutron capture therapy (BNCT), a binary method for cancer treatment that employs the thermal neutron capture reaction of ¹⁰B isotope to kill tumor cells by means of an intracellular fission process [35]. We have been interested in the synthesis of carborane BODIPY derivatives for PDT applications by functionalization of the meso or pyrrole sites of BODIPY with carborane polyhedral compounds [36-38]. In continuation of our work in this area, the functionalization of the BF₂ fragment in BODIPY with carborane clusters via the substitution of fluorine with the corresponding carborane O-nucleophiles was studied. Such reactions were not described in the literature.

Results and Discussion

Synthesis

To study the introduction of carborane O-nucleophiles to the BODIPY boron center available pyrrole-unsubstituted 8-aryl-substituted BODIPYs such as 8-phenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (1), 8-p-bromophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (2), and 8-pentafluorophenyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (3) prepared according to reported procedures [39-41] were initially used as the starting compounds for the envisaged functionalization with 1-hydroxymethyl-o-carborane (4) or 1,2-bis(hydroxymethyl)-o-carborane (5). The reactions of BODIPYs 1–3 with carborane 4 (molar ratio 1:1) were conducted in CH₂Cl₂ under argon at room temperature via the activation of the BODIPY B–F bond with AlCl₃ as Lewis acid catalyst [42,43] within 15–20 min followed by the treatment of the reaction mass with carborane 4 to form dark orange 4-carborane-substituted BODIPY derivatives 6–8 in 35–54% yields (Scheme 1). Using the same synthetic method, the reactions of BODIPYs 1–3 also successfully proceeded with carborane 4 (molar ratio 1:2) (Scheme 1) in CH₂Cl₂ to produce the 4,4-dicarborane-substituted BODIPY derivatives 9–11 in 75–84% yields (Scheme 1).

Under the conditions developed for the preparation of carborane-substituted BODIPYs from carborane 4, the reaction of carborane 5 with BODIPYs 1–3 in CH₂Cl₂ at ambient temperature proceeded less selectively and led to mixtures of boronated BODIPYs despite the increased amount of carborane 5 used in the reactions (Scheme 1).

As a result, BODIPYs 12–14 formed via the intramolecular cyclization of diol 5 with the boron center of BODIPY were obtained in yields of 34–39% along with monocarborane-substituted BODIPYs 15–17 in 12–16% yield and bis(carboranyl)-substituted BODIPYs 18–20 in 23–28% yield, respectively. For the isolation of pure compounds column chromatography on silica gel was performed and all compounds were obtained and characterized (Supporting Information File 1). We also studied the reactivity of the pyrrole-substituted BODIPY 8-pentafluorophenyl-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (21) [44] towards carboranes 4 and 5. The reaction between BODIPY 21 and carborane 4 (at a molar ratio of 1:1 or 1:2) proceeded cleanly in CH₂Cl₂ at ambient temperature after the activation of the B–F bond with AlCl₃ and was completed in 10 min to give the 4-monosubstituted derivative 22 in 48% yield while the disubstituted compound 23 was obtained with a yield of 72% (Scheme 2).

When performing the substitution reaction of the fluoride in BODIPY 21 with carborane 5 using the same reaction conditions a mixture of monosubstituted carborane BODIPY 24 (34% yield) and dicarborane-substituted BODIPY 25 (47% yield) was obtained (Scheme 2). It should be noted that in the case of pyrrole-substituted BODIPY 21 at any ratio of AlCl₃ (from 1 to 2 equivalents) and carborane 5 (from 1 to 5 equivalents), no formation of the cyclized product through reaction of both hydroxy groups of the carborane with the boron atom in BODIPY was observed. The reason for the difference in reactivity when using BODIPY 21 is apparently related to steric hindrance by methyl groups in the BODIPY 3,5-positions.

Spectroscopic data

All synthesized compounds were isolated by column chromatography and their structures were fully characterized by UV–vis, IR and ¹H, ¹¹B, ¹¹B{¹H} NMR spectroscopies and ESI mass spectrometry. The IR spectra of compounds 6–11 and 12–20 showed stretching bands in the region 2573–2590 cm⁻¹ and 1378–1390 cm⁻¹ attributed to BH and B–O groups, respectively. The IR spectra of BODIPYs 15–20, 24, 25 containing an unsubstituted carborane hydroxy group display a characteristic OH absorption band at 3362–3446 cm⁻¹. Absorption bands at 1556–1580 cm⁻¹ correspond to C=C and C=N stretching vibrations and bands in the range of 1158–1186 cm⁻¹ are attributable to B–F stretching vibrations (compounds 6–8, 15–17, 22, 24). The ¹H NMR spectra further supported the structure of the synthesized compounds. The hydroxy protons of compounds 15–20 as well as for compounds 24 and 25 appear as broad singlets at δ = 4.10–4.42 ppm. The signals of the carborane CH protons in compounds 6–11 and 22 were observed at δ = 4.02–4.25 ppm as broad signals. The ¹H NMR spectra show the signals of the CH₂OB protons at 3.39–4.38 ppm as singlets for compounds 6–14. The expected signals with appropriate multiplicities were observed for pyrrole CH protons in the range of δ = 6.59–8.01 ppm and manifested themselves as singlets, doublets or as doublet of doublets (see Supporting Information File 1 for details). The protons of pyrrole methyl groups in BODIPYs 22–25 appeared as singlets in the region of δ = 2.46–2.60 ppm. The ¹¹B{¹H} NMR spectra also confirmed the formation of the expected compounds, showing broad resonances in the region from δ = 0.5 to −13.9 ppm for carborane BODIPY derivatives 6–20 and 22–25. The ¹¹B NMR spectra of the prepared BODIPY derivatives display doublets or broad singlets between δ = 0.5–1.8 ppm.

The UV–vis spectra in CH₂Cl₂ of all the prepared compounds are characterized by the presence of two absorption bands (Figure 1). However, the bands of compounds containing a pentafluorophenyl substituent (8, 11, 14, 17, 20, 22–25) are red-shifted (460–480, 518–520 nm) compared to those with phenyl or p-bromophenyl fragments (6, 7, 9, 10, 12, 13, 15, 16, 18, 19). The absorption bands of the latter compounds are observed in the ranges of 340–360 and 500–505 nm. This phenomenon reflects the influence of fluorine atoms on the HOMO–LUMO energy gap. Modifications of the starting BODIPYs 1, 2, 3 and 21 with carboranes 4 or 5 did not lead to a significant change in the position of the absorption bands but in the case of products 22–25 an increase of the extinction coefficient ε value by one and a half times was observed.

To determine the fluorescence quantum yields (Φ_fl) and Stokes shifts, additional UV–vis (Figure S67, Supporting Information File 1) and fluorescence (Figure 2) spectra were recorded in acetonitrile at ambient temperature for all compounds. The data are summarized in Table 1. The consistently higher fluorescence quantum yields observed for BODIPY derivatives with the 8-pentafluorophenyl group (8, 11, 14, 17, 20, 22–25) compared to their phenyl and p-bromophenyl analogs (6, 7, 9, 10, 12, 13, 15, 16, 18, 19) can be explained by the strong electron-withdrawing character of the pentafluorophenyl group. This suppresses the photoinduced electron transfer from the aryl ring in the meso-position to the excited BODIPY core. Additionally, the steric bulk of the ortho-fluorine substituents in compounds 8, 11, 14, 17, 20, 22–25 restricts rotation of the meso-aryl ring, minimizing non-radiative vibrational relaxation and further increasing the emission efficiency [45]. Notably, the unsubstituted phenyl derivatives 6, 9, 12, 15, 18 showed intermediate fluorescence quantum yields between the values for the p-bromophenyl analogs 7, 10, 13, 16, 19 and pentafluorophenyl analogs 8, 11, 14, 17, 20, 22–25. The lower fluorescence quantum yield of the former relative to the phenyl analogs can be explained by the effect of the heavy bromine atom, which strengthens the spin–orbit coupling and promotes the intersystem crossing to the triplet manifold.

The Stokes shifts ranged from 482 to 1118 cm⁻¹, falling within the typical range reported for BODIPY derivatives [46]. The smallest Stokes shifts were observed for the 8-pentafluorophenyl derivatives 8, 11, 14, 17, 20, 22–25, which is consistent with the restricted rotation of the meso-aryl ring discussed above. The largest Stokes shifts were found for compounds 12–14, which contain the 1,2-di(oxymethyl)-o-carborane moiety. This observation aligns with the low fluorescence quantum yields of these derivatives, as the substantial Stokes shifts indicate extensive excited-state reorganization and enhanced non-radiative decay. The rigid cyclic linkage in compounds 12–14 creates steric strain that distorts the BODIPY core, promoting energy dissipation through non-radiative channels [47].

The molecular structure of compounds 8, 11, 14, 18 and 23 was determined by means of single crystal X-ray diffraction studies (Figure 3). Crystal data and structure refinement parameters of compounds 8, 11, 14, 18 and 23 are presented in Table S1 (Supporting Information File 1).

Conclusion

In summary, carborane BODIPY-based compounds have attracted attention due to their promising potential of applications ranging from materials to biology and medicine. In this work a series of carborane-substituted BODIPYs was synthesized for the first time by the substitution of the fluoride atoms in BODIPYs with carborane O-nucleophiles. The synthetic method includes the cleavage of boron–fluorine bonds in BODIPYs under the action of AlCl₃ and treatment of the reaction mass with 1-hydroxymethyl- or 1,2-dihydroxymethyl-o-carboranes in CH₂Cl₂. The structure of all prepared compounds was fully characterized. It has been revealed that reaction selectivity depends on the carborane structure and is non-selective in the case of 1,2-dihydroxymethyl-o-carborane. The results described in this work demonstrated the way for modification of BODIPY core with carborane polyhedra via the employment of fluoride atoms substitution.