Synthesis and Regioselective Functionalization of Perhalogenated BODIPYs

Abstract

Three perhalogenated BODIPYs (1b–3b), bearing chloro and bromo groups at all carbon positions, were synthesized and characterized. The reactivity of BODIPY 3b was investigated under Stille cross-coupling reactions, and single crystal X-ray analysis was used to confirm the regioselectivity of the reactions. Further substitution at the boron atom produced nona-functionalized BODIPYs 7a,b, which show 676 and 739 nm emissions with 91 and 100 nm Stokes shifts, respectively.

4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (known as boron-dipyrromethene or BODIPY) dyes have attracted growing interest both in the academic and industrial fields. This is due to their remarkable properties, including strong absorptions and sharp emissions in the UV/Vis region, relatively high photostability and solubility, and ease of tunability of their physicochemical properties.¹ Over the past three decades, a large number of new BODIPYs were synthesized, characterized and investigated as fluorescent labelling agents for proteins or DNA,² as biological imaging probes,³ in dye-sensitized solar cells (DSSCs),⁴ and as photodynamic therapy (PDT) sensitizers.⁵

To have access to a variety of BODIPYs, efficient synthetic methodologies toward halogenated BODIPY platforms⁶ for subsequent functionalization through diverse reactions, are of great interest. Since the first halogenated (2,6-dibromo) BODIPY⁷ was synthesized by using Br₂ in dichloromethane, a number of versatile halogenated BODIPYs were reported over the last two decades. These can be prepared by direct halogenation at the BODIPY core,⁸ or by introducing the halogen group in pyrrole⁹ or dipyrromethane precursors.¹⁰ Such halogenated derivatives can be the precursors of a wide range of functionalized BODIPY dyes for various applications, via Pd(0) catalyzed cross-coupling reactions (e.g., the Suzuki, Stille, Heck or Sonogashira reactions) and/or substitution reactions with C-, N-, O-, or S-nucleophiles.¹¹ On the other hand, halogen groups can be selectively introduced into the 3,5-positions,^10a the 2,6-,^7,12 1,7-,¹³ and 8-position¹⁴, allowing the subsequent introduction of various functional groups to specific positions by subsequent Pd(0) cross-coupling reactions or/and substitution reactions. The platforms with 3,5-halogens^10a or/and 8-halogens¹⁴ have attracted considerable interest due to the large distribution of the HOMO and LUMO at the 3,5-positions and 8-position, respectively.^1d The first 3,5-dichloro-BODIPY was reported in 2005^10a and 8-halogenated BODIPYs were reported recently, prepared by treating dipyrroketones with POCl₃ (POBr₃) or COCl₂.^16a,b Such platforms provide a facile way for the functionalization of the 3,5-α positions and the 8-meso position, which significantly affect the properties of BODIPYs, including quantum yield, absorption, and fluorescence, by changing their HOMO and LUMO characteristics.

Including the boron atom, the BODIPY core can accommodate 9 halogen atoms. Previously, we reported a series of carbon-polychlorinated BODIPYs (di-, tri-, tetra-, and penta-) prepared by direct chlorination of the BODIPY core using trichloroisocyanuric acid (TCCA)/acetic acid.¹⁵ The polychlorinated BODIPYs can also be obtained from a dipyrromethane precursor by reaction with COCl₂/CHCl₃.¹⁶ The chlorinated BODIPYs show high reactivity and regioselectivity in nucleophilic substitutions and Pd(0)-catalyzed Stille and/or Suzuki cross-coupling reactions. The reactivity of the chloro groups on the different positions of BODIPYs was investigated, and shown to decrease in the order 8-meso-Cl > 3,5-α-Cl > 2,6-β-Cl, which allows the stepwise functionalization of BODIPYs at the 8 position, 3,5 positions, and 2,6 positions.¹⁵

To the best of our knowledge, perhalogenated BODIPYs have not so far been reported. Extending our previous work, herein we now report the synthesis of three nona-halogenated BODIPYs, 1b, 2b, and 3b starting from 8-chloro-BODIPY 1a, 2,6,8-trichloro-BODIPY 2a and 2,3,5,6,8-pentachloro-BODIPY 3a, respectively. The reactivity and selectivity of BODIPY 3b was investigated by using Stille cross-couplings at the carbon positions and substitution reactions at the boron center. Our studies show that the reactivity order of the halogens under these conditions is: 8-Cl ≈ 1,7-Br > 3,5-Cl > 2,6-Cl > 4,4’-F.

Perhalogenated BODIPYs 1b–3b were synthesized by bromination of the corresponding chloro-BODIPYs, as shown in Scheme 1. The starting 8-chloro-BODIPY (1a)^14a was chlorinated using TCCA in acetic acid to give 2a and 3a in 73 and 81% yields,¹⁵ respectively. Further chlorination at the 1,7-positions was unsuccessful under a variety of conditions, including NCS/THF and TCCA/acetic acid. Therefore, Br₂/CH₂Cl₂ was selected for the bromination of the unsubstituted BODIPY positions of 1a–3a. Treatment of BODIPYs 1a–3a with a large excess of Br₂ in CH₂Cl₂ (up to 200 equivalents) at room temperature overnight, afforded the corresponding nonahalogenated BODIPYs 1b–3b as the only products, in 78–84% yields. The ¹H NMR spectra of 1b–3b showed complete disappearance of all the pyrrolic protons. Furthermore, significant differences were observed in the absorption spectra of 1b–3b relative to the starting BODIPYs 1a–3a in CH₂Cl₂. While 1b and 2b showed absorptions red-shifted by 52 and 15 nm, respectively, the absorption of 3b showed a 9 nm blue-shift in agreement with previous results.^8a The molecular structures of 1b–3b were further confirmed by X-ray analysis, as shown in Figure 1. In all three cases, the 11-atom dipyrrole unit is nearly planar, having mean deviation 0.016 Å in 1b, 0.035 Å in 2b and 0.035 Å in 3b. The boron atom lies slightly out of this plane by 0.171 Å, 0.195 Å and 0.175 Å for 1b, 2b, and 3b, respectively. The C-Br distances in 1b–3b are within the range 1.842(2) – 1.862(3) Å, with a mean value of 1.853 Å, while the C-Cl bonds are in the range 1.695(4) – 1.712(4) Å with mean 1.703 Å. The longer C-Br bonds are expected to be more reactive and less selective in the oxidative addition of Pd(0) compared with the C-Cl bonds, therefore platform 3b was chosen for studies of regioselectivity in Pd(0)-catalyzed cross-coupling reactions.

Scheme 1.

Synthesis of perhalogenated BODIPYs 1b–3b.

Figure 1.

X-ray structures of perhalogenated BODIPYs 1b–3b, with 50% ellipsoids.

Due to the mild base-free reaction conditions and general scope, the Stille reaction¹⁷ is particular attractive among the palladium-catalyzed cross-coupling reactions for investigation of the selectivity of different halogen groups on BODIPY 3b. Upon treating BODIPY 3b with 1 equivalent of 2-(tributylstannyl)thiophene or tributylphenyltin in the presence of Pd(PPh₃)₄ (3 mol%) in refluxing toluene, TLC and MS both indicated a tri-coupled molecule as the major product, along with a large amount of starting BODIPY. This result suggested similar reactivity of three halogenated positions, potentially the 1,7,8-positions, based on previous studies on the reactivity of 3a.¹⁵ When 4 equivalents of tin reagent were used and the mixture was refluxed overnight, the tri-coupled BODIPYs 4a,b were obtained as the major products (Scheme 2) via regioselective coupling at the 1,7,8-positions, and isolated in 57–71% yields.

Scheme 2.

Regioselective cross-coupling reactions of BODIPY 3b.

The structures of these products were confirmed by X-ray analysis, as shown in Figure 2. In the structure of 4a, the 12-atom BODIPY core is nearly planar, with mean deviation 0.021 Å. The three phenyl planes form dihedral angles in the range 63.5–66.6° with it. BODIPY 4b has a very similar structure, with the 12 atoms of the BODIPY core exhibiting mean deviation 0.049 Å and the three disordered thiophene rings forming dihedral angles in the range 60.3–64.0° with it.

Figure 2.

X-ray structures of BODIPYs 4a,b and 5a,b with 50% ellipsoids. Only one orientation of the disordered substituents is shown.

The 1,3,5,7,8-pentaphenyl-(pentathienyl)-2,6-dichloro-BODIPYs 5a–b were obtained regioselectively in 75–92% yields by treating BODIPYs 4a–b with 10 equivalents of tin reagent under similar conditions, as shown in Scheme 2. This result is in agreement with previous investigations showing that Stille coupling occurs preferentially at the most reactive 3,5-chloro groups rather than at the 2,6-chloros.^15,16 X-ray crystallography was used to confirm the regioselectivity of these reactions (Figure 2). The core of BODIPY 5a has a conformation similar to those of 1b, 2b, and 3b, with the B atom lying 0.183 Å (average of two independent molecules) out of the plane of the other 11 atoms. The phenyl groups are ordered in one molecule and disordered in the other, and in the ordered one they form dihedral angles in the range 52.5–72.1° with the core. BODIPY 5b has a core conformation similar to 5a, but with the B atom having a smaller out-of-plane deviation, 0.106 Å. Four of the five thiophene rings are disordered, with the ordered one at an α position and forming a small dihedral angle (27.4°) with the BODIPY core. The disordered thiophene substituents have variable conformations, forming dihedral angles in the range 52.2–73.2° with the core.

The global C-C coupling reactions were accomplished by using chloro[(tricyclohexylphosphine-2-(2’-aminobiphenyl) palladium [Pd(PCy3)G2] as the catalyst,¹⁸ in the presence of 10 equivalents of 2-(tributylstannyl)thiophene to provide the corresponding 1,2,3,5,6,7,8-heptacoupled products 6a,b in good to excellent yields (76%–95%), as shown in Scheme 3. The structures of these BODIPYs were confirmed by NMR and MS (see Supporting Information). Further functionalization of BODIPYs 6a,b at the boron center using an excess of trimethylsilyl cyanide in the presence of BF₃•OEt₂ as catalyst¹⁹ produced the corresponding nona-functionalized BODIPYs 7a,b in 92–93% yields, as shown in Scheme 4. The formation of 7a,b was clearly indicated by ¹¹B-NMR which showed disappearance of the BF₂ triplet at ca. δ 0.9 ppm and the appearance of a characteristic singlet at ca. δ −16 ppm for the B(CN)₂ group.²⁰

Scheme 3.

Stille cross-coupling reactions of BODIPYs 5a,b.

Scheme 4.

Boron-substitution reactions of BODIPYs 6a,b.

The spectroscopic properties of the newly generated BODIPYs, including the UV-Vis absorption, emission, molar extinction coefficient and quantum yield, were investigated in dichloromethane solution and the results are summarized in Table 1 (see also Supporting Information). All BODIPYs show typical strong absorption bands (log ε = 4.48–5.02) corresponding to the S₀–S₁ transition. The Stokes shifts vary significantly (8–100 nm) depending on the substituent groups on the BODIPY platform, and were largest for the B(CN)₂-functionalized BODIPYs bearing 2,6-thienyl groups. Similar enhancement of Stokes shifts have been reported for B(CN)₂-functionalized-BODIPYs¹⁹ and for thienyl-functionalized BODIPYs.^15,16 From 1b to 3b, the decreasing number of bromo substituents induced slight blue-shifts (3–12 nm) in the absorption and emission spectra. The introduction of phenyl or thienyl groups at positions 1,7,8 of BODIPY 3b caused small red-shifts in the absorption and emission bands (3–26 nm), in part due to the large dihedral angles of the aryl groups at these positions, in the order of 60–67°, as seen in the crystal structures (Figure 2). On the other hand, functionalization at the 3,5-positions caused larger red-shifts (up to 121 nm for 5b), as previously observed,^15,16,21 particularly for the thienyl-substituted BODIPYs. In addition, the 3,5- and 2,3,5,6-thienyl functionalized BODIPYs typically show larger Stokes shifts than the phenyl analogues, due to increased geometry relaxation.²² However, the thienyl groups also greatly decreased the quantum yields of the functionalized BODIPYs (< 0.1) due to their greater freedom of rotation compared with phenyl, which increases the amount of energy lost to non-radiative decay to the ground state.

Table 1.

Spectroscopic properties of BODIPYs in dichloromethane at room temperature.

BODIPY	Absorption λmax (nm)	Log ε (M−1cm−1)	Emission λmax (nm)	Φf[a]	Stokes shift (nm)
1b	556	5.02	572	0.17	16
2b	553	5.01	568	0.14	15
3b	546	4.87	560	0.18	14
4a	549	4.77	563	0.57	14
5a	564	4.85	596	0.39	32
6a	581	4.66	666	0.08	85
7a	585	4.48	676	0.06	91
4b	572	4.72	580	<0.003	8
5b	633	4.56	681	0.02	48
6b	643	4.74	713	0.007	70
7b	639	4.48	739	0.005	100

^[a]Rhodamine B (0.4 in methanol)²³ for 1b–3b and 4a; cresyl violet (0.55 in methanol)²⁴ was used as standard for 4b and 5a–7a, and methylene blue (0.03 in methanol)²⁴ for 5b–7b.

In summary, perhalogenated BODIPYs 1b–3b bearing chloro or bromo groups at all carbon-positions of the BODIPY platform were synthesized in good yields, via bromination of regioselectively chlorinated BODIPYs. The regioselective nonafunctionalization of BODIPY 3b was investigated and confirmed by X-ray crystallography and/or NMR spectroscopy and MS spectrometry. Using Pd(0)-catalyzed Stille reactions, excellent regioselectivity was observed for the 1,7-dibromo-8-chloro groups over the 3,5-dichloro with formation of 4a,b and 5a,b, and also for the 3,5-dichloro over the 2,6-dichloro groups with formation of 6a,b. Under the Stille coupling conditions the BF₂ moiety was unreactive; however in the presence of TMSCN/BF₃•OEt₂ it was converted into the corresponding B(CN)₂-functionalized BODIPYs in high yields.

The phenyl-functionalized BODIPYs show moderate quantum yields (0.57 and 0.39 for 4a and 5a, respectively) while the thienyl-substituted BODIPYs showed the largest red-shifted absorptions and emissions, with large Stokes shifts and low quantum yields (< 0.1). The nona-functionalized BODIPYs had the largest Stokes shifts (91–100 nm) and slightly reduced quantum yields relative to the BF₂ derivatives.