B-spiroBODIPYs as a fluorophore responsive to hydrogen bond donors

Abstract

Boron dipyrromethene (BODIPY) dyes possess excellent photophysical properties and are extensively used in chemical biology and materials science. While peripheral functionalisation of the dipyrromethene core is well established, modification at the boron centre has remained limited. Here, we demonstrate an Au-catalysed modulation of the boron centre, enabling the synthesis of B-spiroBODIPYs with a 1,3-dioxinone moiety on boron. The resulting B-spiroBODIPY exhibits solvent-dependent fluorescence arising from hydrogen-bonding interactions at the carbonyl oxygen on the 1,3-dioxinone moiety, offering a versatile platform for stimulus-responsive fluorescent probes.

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Introduction

Boron dipyrromethene (BODIPY) and its derivatives are attractive organic dyes that display intense visible-light absorption and bright emission with high quantum yields.¹ Owing to these properties, BODIPY dyes have been widely applied in chemical biology and materials science.² BODIPY derivatives with appropriate functional groups can alter their photophysical properties in response to external stimuli such as pH,³ temperature,⁴ polarity^4a,5 and viscosity.^4a,6

The introduction of functional groups onto the BODIPY unit has been conducted based on the versatile reactivity of the dipyrromethene skeleton. The peripheral positions of the BODIPY unit can be selectively manipulated through reactions with electrophiles, nucleophiles, radicals and transition metal catalysts, enabling precise modulation of their physical properties (Fig. 1a).⁷

Fig. 1 Functionalisation of BODIPYs and the concept of this work.

On the other hand, functionalisation of the boron centre of BODIPY offers an attractive alternative strategy. It enables incorporation of additional features, including enhanced stability, solubility and modulated aggregation behaviour, while leaving the inherent optical properties of the BODIPY scaffold essentially intact (Fig. 1a).⁸ However, the modification of the boron centre of the BODIPY unit has not been explored until recently.

The strategies for boron functionalisation can be divided into two types: one involves nucleophilic substitution on the boron atom,⁹ and the other is B–O bond cleavage by photoirradiation.¹⁰ In the case of nucleophilic substitution, the use of hard Lewis acids⁹ or hard nucleophiles⁹ is required to install the substituents on the boron centre. In addition, only BODIPYs with (pseudo)halogens on boron can be employed. Photoinduced B–O bond cleavage of O-BODIPY can generate the corresponding borenium cation, which is utilised as a photocage in cell biology.¹⁰ However, only hydroxy and alkoxy groups from solvents can be introduced on the boron centre.

In this work, we advance the concept of modulating BODIPY properties by reconfiguring its boron coordination environment. Further transformations of substituents on the boron centre provide a versatile strategy for introducing new functionalities and tuning the behaviour of BODIPY dyes (Fig. 1b). Herein, we have successfully developed an Au-catalysed modulation at the boron centre of COO-BODIPY, affording B-spiroBODIPYs with a 1,3-dioxinone moiety on the boron centre (Fig. 1c). The obtained B-spiroBODIPY exhibits solvent-dependent fluorescence through hydrogen bonding between its carbonyl oxygen and solvent molecules, underscoring its potential as a stimulus-responsive fluorescent probe.¹¹

Results and discussion

We first synthesised COO-BODIPY 2a derivatives from F-BODIPY 1a with corresponding carboxylic acids in the presence of BCl₃ and triethylamine (Scheme 1).⁹ Treatment of 2a with the combination of AuCl(IPr) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) and silver triflate in the presence of tetrabutylammonium triflate afforded B-spiroBODIPY 3a in 80% yield (Scheme 1).¹² This protocol was applied to BODIPY 2b and tetramethylBODIPY 2c, providing corresponding B-spiroBODIPYs 3b and 3c in 92% and 75% yields, respectively.

Scheme 1 Synthesis of B-spiroBODIPY 3 via Au-catalysed hydration and cyclisation.

The structure of 3a was unambiguously determined by X-ray crystal analysis (Fig. 2). The single crystal of 3a was obtained by vapour diffusion of hexane to a solution of 3a in dichloromethane. In BODIPY 3a, the 1,3-dioxinone moiety is orthogonal to a BODIPY subunit. The mean plane deviation (MPD) of the BODIPY subunit was 0.031 Å, indicating that the spiro structure did not affect the planarity of the BODIPY core. It is worth noting that the distance between a carbon atom in dichloromethane and an oxygen atom at the carbonyl group was 3.094 Å, which was shorter than the sum of van der Waals radii of carbon (1.70 Å) and oxygen (1.52 Å). These results suggest that the carbonyl group in 3a forms hydrogen bonding with dichloromethane co-crystallised in the crystal 3a·CH₂Cl₂. Single crystals 3a·CHCl₃ and 3a·HFIP were also obtained by evaporation of a chloroform solution of 3a and vapour diffusion of water into a solution of 3a in 1,1,1,3,3,3-hexafluoroisopropan-2-ol (HFIP). The distance between the carbon atom of chloroform and the carbonyl oxygen was 2.979 Å, whereas the distance between the oxygen atom of HFIP and the carbonyl oxygen was 2.645 Å. Furthermore, the C=O bond lengths in 3a·CH₂Cl₂, 3a·CHCl₃ and 3a·HFIP were 1.216 Å, 1.220 Å and 1.236 Å, respectively. These findings indicate that 3a interacts tightly with HFIP through hydrogen bonding with its carbonyl oxygen.¹³

Fig. 2 X-ray crystal structures of 3a·CH₂Cl₂, 3a·CHCl₃ and 3a·HFIP. Thermal ellipsoids are shown at 50% probability. Hydrogen atoms, except for those in solvents, and mesityl groups are omitted for clarity.

We examined the functionalisation of the obtained B-spiroBODIPY derivatives 3 (Scheme 2). The reaction of 3a with N-iodosuccinimide (NIS) in acetic acid promoted selective iodination on the central carbon atom of the 1,3-dioxinone moiety in 72% yield.¹⁴ The subsequent Suzuki–Miyaura coupling of 4a provided the arylated product 5a in 53% yield. In sharp contrast, iodination of 3c proceeded on the BODIPY subunit under the same conditions to afford mono- and di-iodinated BODIPY 6c and 7c in 45% and 55% yield, respectively. These results suggest that the most nucleophilic site is on the 1,3-dioxinone moiety in 3a but on the BODIPY framework in 3c. These results demonstrated that regioselective functionalisation of B-spiroBODIPYs 3 enables further elaboration of the BODIPY and 1,3-dioxinone moieties to fine-tune their properties.

Scheme 2 Functionalisation of B-spiroBODIPY 3.

We measured absorption and emission spectra of COO-BODIPY 2a and B-spiroBODIPYs 3 in CH₂Cl₂ (Fig. 3). Both COO-BODIPY 2a and B-spiroBODIPYs 3 exhibit intense absorption bands around 505 nm and emission bands around 520 nm, regardless of the substituent on the boron atoms. The absorption and fluorescence spectral shapes of 2a and 3 are comparable to those of BODIPY 1a.¹⁵ However, the quantum yields Φ_F of 3a and 3b were 0.078 and 0.069, respectively, which are markedly different from those of 2a (Φ_F = 0.74) and 3c (Φ_F = 0.79), demonstrating the efficient photophysical modulation by functionalisation at the boron centre. The decrease in fluorescence quantum yield can be explained by intramolecular charge transfer from the electron-donating 1,3-dioxinone moiety to the electron-accepting BODIPY subunit.

Fig. 3 Absorption and emission spectra of 2a and 3 in CH₂Cl₂. Absorption and fluorescence spectra were measured with 10⁻⁵ M solutions.

We evaluated the solvent effect on the photophysical properties of 3a (Table 1). The shape of the absorption and emission spectra displayed almost no change in various solvents (Fig. S41 and S42). However, the emission quantum yield was significantly modulated by the solvents. In chloroform, the quantum yield increased to 0.30 compared to that in CH₂Cl₂ (0.078). While the fluorescence intensities were comparable in apolar solvents such as CH₂Cl₂, toluene, hexane and Et₂O, fluorescence became slightly stronger in alcohols. We hypothesise that hydrogen bond donors interact with the carbonyl oxygen on the 1,3-dioxinone moiety, thereby enhancing the fluorescence. We then chose HFIP as a strong hydrogen bond donor,¹³ which dramatically enhanced the fluorescence quantum yield to 0.93. In addition, we measured absorption and emission in the presence of water in acetonitrile (Fig. 4). As water content increased, the emission quantum yield was enhanced from 0.019 to 0.16. This result can also be attributed to the hydrogen bonding interaction with water.

Fig. 4 Fluorescence spectra in MeCN–H₂O mixture containing X% (w/w) H₂O (X = 0, 10, 50, 90).

Table 1 Photophysical properties of 3a in various solvents

Solvent	ΦF	<τ>/ns	kf/10^7 s^−1	knr/10^8 s^−1
Quantum yields and fluorescence lifetimes were obtained with 10^−5 M solutions.
Et2O	0.030	3.8	0.79	2.5
toluene	0.071	1.7	4.2	5.5
CH2Cl2	0.078	1.1	6.8	8.0
IPA	0.22	3.0	7.3	2.6
CHCl3	0.30	4.5	6.7	1.6
HFIP	0.93	10.4	9.0	0.067

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We also determined fluorescence lifetimes in different solvents to estimate the rates of radiative and non-radiative decay. The fluorescence decay profiles were fitted with a double-exponential function to determine the average fluorescence lifetimes (Fig. S43 and S44). While the fluorescence lifetimes in toluene and CH₂Cl₂ were 1.7 ns and 1.1 ns, respectively, that in HFIP was much longer (10.4 ns). The k_f value in Et₂O was an order of magnitude smaller, resulting in significantly reduced fluorescence intensity. The k_f values were comparable in other solvents. However, the k_nr value in HFIP was one hundredth of the value measured in other solvents. We considered that hydrogen bonding stabilises the molecular orbital of the 1,3-dioxinone moiety, thus suppressing intramolecular charge transfer leading to non-radiative decay.

To verify the presence of hydrogen bonding in solution, we measured the infrared absorption spectra of 3a in various solutions to evaluate the carbonyl stretching vibration (Fig. 5). In Et₂O, where the fluorescence quantum yield was the lowest, the C=O stretching vibration was observed at 1716 cm⁻¹. As the fluorescence quantum yield increased, the C=O stretching band shifted to lower wavenumbers. The C=O stretching vibration peak was detected at 1632 cm⁻¹ in HFIP. These observations clearly indicate that the carbonyl group of 3a forms hydrogen bonds with the solvent.

Fig. 5 IR spectrum of 3a in various solvents (ca. 0.6 mM).

To gain a deeper insight into the solvent effect on 3a, we conducted DFT calculations.¹⁶ The structure optimisations were conducted at the B3LYP/6-31+G(d,p) level of theory (Fig. 6). The single-point calculations were performed at the B3LYP/6-311+G(d,p) level of theory using the optimised structure or the crystal structure. Both HOMO and LUMO of 2a were localised on the BODIPY subunit, which were almost identical with those of BODIPY 1a.¹⁷ Conversely, the HOMO (−6.33 eV) and HOMO−1 (−6.42 eV) of 3a were almost degenerated, which were delocalised on both BODIPY and 1,3-dioxinone subunits. These differences in molecular orbitals contributed to the photophysical properties before and after spiro cyclisation. The LUMO of 3a was rather localised on the BODIPY subunit. Therefore, the partial orbital separation in 3a indicates the existence of intramolecular charge transfer character in the excited state, which contributes to its less emissive feature. In contrast, the HOMO and LUMO of 3c were destabilised by electron-donating methyl groups, resulting in lifting the degeneracy between the HOMO (−5.74 eV) and HOMO−1 (−6.30 eV). Accordingly, the HOMO and LUMO of 3c were almost identical with those of BODIPY 1a and 2a, resulting in the retrieval of the emissive nature of BODIPY.

Fig. 6 Molecular orbitals of COO-BODIPY 2a and B-spiroBODIPY 3a, 3c, and 3a·HFIP (unit: eV).

The dihedral angles between the mean planes of the BODIPY and 1,3-dioxinone subunits were 83.0° and 90.0° in the optimized structures of 3a and 3c, respectively. We concluded that the dihedral angles did not significantly affect the degeneracy of the HOMO and HOMO−1. The difference in the frontier orbitals of 3a and 3c can also explain the regioselectivity of electrophilic iodination observed in Scheme 2. The HOMO of 3a exhibits high MO coefficients on the 1,3-dioxinone subunit, which undergoes the electrophilic iodination. In contrast, the HOMO of 3c is mainly located on the BODIPY subunit, resulting in β-selective iodination of the BODIPY core.

In the crystal structure of 3a·HFIP, the degeneracy between HOMO and HOMO−1 was lifted, as the molecular orbital derived from the 1,3-dioxinone subunit was substantially stabilised by hydrogen bonding. Consequently, the effect of intramolecular charge transfer was almost diminished in 3a·HFIP, thus improving its fluorescence intensity.

Conclusions

We developed the additional functionalisation of COO-BODIPY 2 to synthesise B-spiroBODIPY via an Au-catalysed hydration and subsequent intramolecular cyclisation. B-spiroBODIPY 3 possessed a 1,3-dioxinone moiety, which can be further transformed by halogenation and cross-coupling reaction. While B-spiroBODIPY 3a exhibited very weak fluorescence in non-hydrogen-bonding solvents, its photophysical properties, including a quantum yield and fluorescence lifetime, were remarkably modulated by hydrogen bond donors. B-spiroBODIPYs with a 1,3-dioxinone subunit are promising as an environment-sensitive dye for fluorescence lifetime imaging microscopy and would be useful in the field of chemical biology.^6a,b,18

Author contributions

H. T. and H. S. designed and conducted the project, prepared the original draft, and finalised the manuscript. A. K. carried out all the experiments, including the synthesis and characterisation. The manuscript was written with contributions from all authors. All authors have approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: Fig. S41–S44, NMR spectra, HR-MS spectra, further experimental details and calculation details. See DOI: https://doi.org/10.1039/d6qo00102e.

CCDC 2523317–2523319 for 3a·CHCl₃, 3a·HFIP and 3a·CH₂Cl₂ contain the supplementary crystallographic data for this paper.^19a–c

Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS) via KAKENHI grants JP20H05862, JP20H05863, JP22H04974 and JP24K17675. This work was also supported by MEXT (Japan) via the Leading Initiative for Excellent Young Researchers (grant: JPMXS0320220200). H. T. acknowledges the Hibi Science Foundation for financial support. We gratefully acknowledge Prof. Shigehiro Yamaguchi and Prof. Soichiro Ogi (Nagoya University) for their assistance with the solution-phase IR spectroscopy measurements.

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