Synthesis and Regioselective Functionalization of Tetrafluorobenzo-[α]-Fused BOPYPY Dyes

Abstract

The synthesis of a new bis-BF₂ tetrafluorobenzo-[α]-fused BOPYPY dye from 4,5,6,7-tetrafluoroisoindole and 2-hydrazinopyrazine is reported. The regioselectivity of nucleophilic substitution reactions at the periphery of the tetrafluorinated BOPYPY and its α-bromo derivative were investigated using N-, O-, S-, and C-based nucleophiles. Among the aromatic fluorine atoms, the F² atom is consistently regioselectively substituted, except when the α-position contains a thiophenol group; in this case, F⁴ is substituted instead due to stabilizing π–π-stacking between the two aromatic groups. The α-bromo BOPYPY derivative also reacts under Stille cross-coupling reaction conditions to produce the corresponding α-substituted product. The spectroscopic properties of these new fluorinated BOPYPYs were investigated and compared with nonfluorinated analogs.

Short abstract

The synthesis and regioselective functionalization of unsymmetric tetrafluorobenzo-[α]-fused-BOPYPYs are reported. These fluorophores feature dual absorptions bands in the region 457−559 nm and relatively large Stokes shifts, in the order of 3000 cm⁻¹. These BOPYPY dyes display low fluorescence quantum yields, due to internal conversion to an excited dark state, due to the lone pair of electrons on the pyrazine nitrogen atom.

1. Introduction

Heterocyclic chromophores have recently been a center of widespread investigations due to their extensive applications in biomedicine and material science.¹⁻⁶ The diverse applications of these molecules demand unique optoelectronic properties and desirable chemical, biological and physical features. As a result, many useful organic fluorophores have been developed in pursuit of new molecules with desired properties.^3,7,8 Among the most recently explored dyes, the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene or boron dipyrromethene dyes (abbreviated BODIPY, Figure 1) have attracted intense research interest owing to their favorable photostability, easy synthesis and structural modifications, and their tunable photophysical properties.^5,9 In particular, BODIPY derivatives bearing two BF₂-complexed groups were recently explored and observed to exhibit near unity fluorescence quantum yields and enhanced photostability as a result of their rigid planar structures.^9,10 Among these, the bis(difluoroboron)1,2-bis((1H-pyrrol-2-yl)methylene)-hydrazine dyes (known as BOPHY, Figure 1) have found applications in multiple areas, including energy-transfer cascades, fluorescence imaging, solar cells, and cancer therapy.¹¹⁻¹⁴ However, some BOPHYs show self-quenching effects and limited solubility as a result of their rigid symmetric cores, leading to reduced fluorescence quantum yields.⁹ To address this challenge, unsymmetric bisBF₂ derivatives, known as BOPPY¹⁵ and BOPYPY¹⁶ (Figure 1), were recently synthesized and observed to display large Stokes shifts and high fluorescence quantum yields both in solution and in the solid state. These unsymmetric bisBF₂ fluorophores are readily prepared in moderate to good yields from condensation of an α-formylpyrrole ring with 2-hydrazinylpyridine (in the case of BOPPY) or with 2-hydrazinylpyrazine (in the case of BOPYPY).^15,16 Both BOPPY and BOPYPY dyes in general show large molar absorptivities, dual absorptions and emissions, and high photostability. In addition, these dyes are reported to exhibit strong solid-state emissions and two-photon absorptions in the near-IR region.¹⁵ Due to the presence of the additional N atom in the pyrazine ring, the absorption and emission of BOPYPY dyes are red-shifted by about 40–60 nm compared with those of the BOPPY analogs.¹⁶ To achieve bathochromic shifts in the absorption and emission bands, benzo-fused BOPPYs with extended π-systems have been recently reported;¹⁷ however, benzo-fused BOPYPY dyes have not yet been investigated.

Figure 1.

Core structures of BODIPY and bisBF₂ derivatives BOPHY, BOPPY, and BOPYPY.

Herein, we report the synthesis of new unsymmetric tetrafluorobenzo-[α]-fused-BOPYPYs 1 and 2, and their regioselective functionalization by nucleophilic substitution reactions (S_NAr) at both the halogenated α-position and the aromatic fluorine sites. The electron-withdrawing fluorine atoms in these molecules further stabilize this type of chromophore relative to the currently known compounds.¹⁸ In addition to improving stability, advantages of introducing a tetrafluorobenzo-fused unit in the chromophore include (1) extending the chromophore π-system leading to longer wavelength absorptions and emissions, (2) allowing direct attachment of molecules via nucleophilic substitutions of one or more fluorine atoms, (3) allowing for¹⁹ F-radiolabeling for dual fluorescence and MRI imaging, and (4) improving solubility.^19,20 In addition, a Stille coupling reaction was investigated on the α-bromo-BOPYPY derivative 2, demonstrating the versatility of regioselective functionalization of this type of chromophore.

2. Results and Discussion

2.1. Synthesis and Structure Characterization

4,5,6,7-Tetrafluorobenzo[c]pyrrole-2-carbaldehyde is a useful starting material for the synthesis of fluorinated benzoporphyrins,¹⁸ perfluoro-benzo[α]-fused BODIPYs,²⁰ and BOPHYs.¹⁹ Since this isoindole 2-carbaldehyde can readily be prepared from commercially available tetrafluorobenzonitrile in 3 steps with an overall yield of 18%, we decided to use it as starting material for the preparation of tetrabenzo-[α]-fused BOPYPY 1 (Scheme 1). We hypothesized that the benzo-fused moiety, as well as the pyrazine unit, would induce large bathochromic shifts on the absorption and emission wavelengths compared with currently known BOPPY and BOPYPYs. Furthermore, it would allow the investigation of aromatic fluorine substitution regioselectivity that is useful for direct conjugation with a variety of molecules to the chromophore for diverse applications.^19,20

Scheme 1. Synthesis of BOPYPY 1 and Its Brominated Derivative 2.

As shown in Scheme 1, the reaction of the tetrafluoroisoindole-2-carbaldehyde with 2-hydrazinopyrazine in the presence of p-toluenesulfonic acid (PTSA), followed by complexation with boron trifluoride etherate (BF₃•OEt₂) in 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), yielded BOPYPY 1 in 31% yield (Scheme 1). Regioselective bromination of BOPYPY 1 using bromine in chloroform²¹ occurred at the most electron-rich α-pyrrolic position, affording 2 in quantitative yield.

The structures of BOPYPYs 1 and 2 were characterized by¹⁹F, ¹¹B, and ¹H NMR spectroscopy (see Figures S1–S6) and HRMS (Figures S68–S69). The ¹⁹F NMR of BOPYPY 1 showed the four aromatic fluorines at −144.31, −147.83, −152.76, and −160.06 ppm, and the two distinct BF₂ groups appear at −141.53 and −144.40 ppm. In the ¹¹B NMR spectrum, two sets of triplets at 1.02 and 3.02 ppm were observed, corresponding to the two BF₂ groups on the 6-membered and the 5-membered rings, respectively, based on previous studies.¹⁹ The ¹H NMR of BOPYPY 1 showed five aromatic protons at 9.16, 8.34, 8.33, 8.26, and 7.86 ppm; the α-pyrrolic proton at 8.34 ppm disappeared upon bromination, to afford BOPYPY 2. Crystals of BOPYPY 1 and its α-bromo derivative 2 suitable for X-ray analysis were obtained by slow diffusion of hexane into dichloromethane (Figure 2). The structures of 1 and 2 (as the substitutionally disordered crystal with the Br atom 67% occupied) have distinct differences and clearly show the asymmetry in the BOPYPY chromophore. In 1, the molecule has a slightly bowed shape, with the central 6-membered C₂BN₃ ring being planar to within an average deviation of 0.02 Å, the F₄Ph group forming a dihedral angle of 2.9° with it, and the pyrazine ring forming a 9.2° dihedral angle with it. The two boron atoms differ in their coordination geometry, with the one in the 6-membered ring having slightly shorter B–N distances (av. 1.556 Å) and slightly longer B–F distances (av. 1.378 Å) than those in the 5-membered ring (1.573 and 1.363 Å, respectively). On the other hand, the bowed shape in 2 is more pronounced than in 1. The central 6-membered ring is nonplanar, with the boron atom lying 0.38 Å out of the plane of the other five atoms, the F₄Ph group forming a dihedral angle of 9.2° with it, and the pyrazine ring forming a 12.4° dihedral angle with it. Furthermore, in the brominated derivative 2, all B–N distances are similar, in the range 1.563(4)–1.568(4) Å, and all B–F distances are equal, in the range 1.363(4)–1.374(4) Å. The C–Br distance is 1.822(3) Å, slightly shorter than C(3)-Br distances on BODIPYs. TD-DFT calculations on the structures of 1 and 2 confirm that the two boron atoms in each compound differ in their geometry, with the 6-membered ring having slightly shorter B–N bond lengths compared to the 5-membered ring. In addition, since the two BF₂ units are on different size rings, our calculations show that the N–B–N angles are around 10° smaller in the 5-membered ring compared with those in the larger 6-membered ring while the F–B–F angles differ only by 1–2°, in agreement with the crystal structures measurements.

Figure 2.

X-ray crystal structures of BOPYPY 1 (left) and its brominated derivative 2 (right) with 50% ellipsoids.

2.2. Nucleophilic Substitution Reactions

Nucleophilic substitutions of halogenated BODIPY derivatives and other chromophores are a convenient methodology for the introduction of various types of nucleophiles, including S-, N-, O-, and C-centered examples, onto a chromophore to modulate its chemical and photophysical properties.^22,23 In particular, the introduction of aromatic fluorines provides a useful strategy for direct conjugation of molecules via S_NAr reactions, under mild conditions. These reactions normally occur via a concerted two-step addition–elimination mechanism by nucleophilic attack on the electron-deficient benzo ring. We have previously reported that a symmetric bis(tetrafluorobenzo-[α]-fused) BOPHY derivative reacts in the presence of S-centered nucleophiles giving the corresponding substituted products with high regioselectivity.¹⁹ Therefore, we investigated the reactivity of unsymmetric BOPYPY 1 in the presence of the reactive 4-methoxythiophenol as the nucleophile (Scheme 2). The reaction occurred smoothly at room temperature overnight with high regioselectivity, giving BOPYPY 3 as the sole product in 68% yield. Minor byproducts containing two nucleophiles were also produced, albeit in low yield, as detected by mass spectrometry. The structure of 3 was confirmed by ¹⁹F, ¹¹B, ¹H NMR, and 2D ¹H–¹⁹F HOESY spectroscopy (see Figures S7–S9,S49) and HRMS (Figure S70). In the ¹⁹F NMR of 3, the three aromatic fluorines appear at −114.66 (F¹), −135.30 (F³), and −145.84 ppm (F⁴) and the two BF₂ groups on the 6- and 5-membered rings at −140.37 and −143.44 ppm, respectively. In the 2D ¹H–¹⁹F HOESY, cross-peaks between F¹ and the meso-H, and between F⁴ and the α-H were observed. The chemical shifts of the α-pyrrolic and meso-protons of BOPYPY 3 did not change significantly upon introduction of the p-methoxythiophenol substituent. In the ¹¹B NMR spectrum, the boron atoms appear as triplets at 1.04 and 2.98 ppm.

Scheme 2. Regioselective S_NAr Reactions of BOPYPY 1 Using 4-Methoxythiophenol.

We have previously observed similar regioselectivity in the S_NAr reactions of a tetrafluorobenzo-[α]-fused BOPHY in the presence of thiols, which occurred exclusively at the F² position.¹⁹ To further understand the experimentally observed regioselectivity, we used DFT calculations to evaluate the charges on the tetrafluoro aromatic carbon atoms using two different schemes: NPA (natural population analysis) and MK (Merz–Singh–Kollman). However, neither of these schemes produced results that were able to explain the experimentally observed regioselectivity. As shown previously,^24,25 the molecular electrostatic potentials (MESPs) at atomic nuclei might be better reactivity descriptors, since these are calculated directly from the electron densities without any additional approximations. These calculations showed that for BOPYPY 1 (see Figure S63), the least negative MESPs are located on the carbons attached to F¹ and F², suggesting that these are the most susceptible to nucleophilic attack, with the F² carbon being slightly more reactive. In agreement with this result, our calculations indicate that the F²-substituted BOPYPY 3 and its F¹-substituted analog have similar energies, with BOPYPY 3 being slightly more stable by approximately 0.5 kcal/mol.

Since increasing the concentration of nucleophile and the reaction temperature resulted in mixtures of products in low yields, we next investigated the regioselectivity of S_NAr reactions on the α-bromo BOPYPY 2, in the presence of S-, N-, O-, and C-centered nucleophiles (Scheme 3).²⁶ As expected, these reactions occurred with high selectivity at the brominated carbon atom bearing the best leaving group.

Scheme 3. Regioselective S_NAr Reactions of BOPYPY 2 with S, O, N, and C Nucleophiles.

The corresponding mono-α-substituted BOPYPYs 4 were isolated after purification by silica gel column chromatography followed by recrystallization. The reaction conditions and the yields obtained in these reactions are summarized in Table 1 and reflect the reactivity of the nucleophile. The most reactive S- and N-centered nucleophiles readily reacted at room temperature in chloroform, while the less reactive O- and C-centered nucleophiles required heating in toluene, affording the corresponding products in moderate to high yields. 4-Methoxythiophenol reacted the fastest with BOPYPY 2 giving BOPYPY 4b in 78% isolated yield, after 1 h at room temperature in chloroform solution. 4-Methylthiophenol and diethylsulfide gave similar high yields of 4c and 4d upon heating at 50 °C for 1 or 3 h, respectively. On the other hand, diethylamine reacted smoothly with BOPYPY 2 at room temperature overnight, affording BOPYPY 4e in 88% yield, while 4-methoxyphenol required higher temperature (80 °C), giving BOPYPY 4a in 54% isolated yield. The carbon nucleophiles 3-ethyl-2,4-dimethylpyrrole and 2,4-dimethylpyrrole also reacted with BOPYPY 2 in toluene at 80 °C for 3–5 h to afford the corresponding BOPYPY derivatives 4f and 4g in 63 and 79% yields, respectively.

Table 1. S_NAr Reaction Conditions and Yields for α-Substituted BOPYPYs 4.

BOPYPY	temp (°C)	time (h)	Nu equiv	solvent	yield (%)
4a	80	3	3.0	toluene	54
4b	r.t.	1	1.1	chloroform	78
4c	50	1	1.5	chloroform	77
4d	50	3	1.5	chloroform	83
4e	r.t.	16	2.0	chloroform	88
4f	80	3	4.0	toluene	63
4g	80	5	4.0	toluene	79

All the monosubstituted derivatives 4 were stable under light, humidity, and air, and their structures were characterized by ¹⁹F, ¹¹B, and ¹H NMR spectroscopy (see Figures S10–S30) and HRMS (Figures S71–S77). In all the ¹⁹F NMR spectra of BOPYPYs 4, the four distinct aromatic fluorines appeared consistently between −138.03 and −160.79 ppm, and the two BF₂ groups at around −136.10 and −145.09 ppm, with the exception of 4f and 4g; in these cases, due to the hydrogen bond interaction between the pyrrolic NH and the neighboring BF₂, the two fluorines on the 6-membered ring BF₂ group show distinct chemical shifts in ¹⁹F NMR spectra. In the ¹¹B NMR spectra, the two distinct triplets appeared at around 0.80 and 3.06 ppm for all the compounds. Slight shifts were observed in the ¹H NMR chemical shifts of the meso-protons. Furthermore, the X-ray crystal structures for BOPYPYs 4a, 4c, 4d, and 4e were obtained and are shown in Figure 3. Interestingly, the 4a molecule has a bowed shape that differs from those of 1 and 2. Its central C₂BN₃ ring is planar to within an average deviation of 0.01 Å, the F₄Ph group forms a dihedral angle of 10.7° with it, and the pyrazine ring is nearly coplanar with it, forming a dihedral angle of only 1.1°. The methoxy substituent is distinctly twisted with respect to the core of the molecule, with a N–C–O–C torsion angle 125.2(7)°. Furthermore, the B–N and B–F distances in 4a do not show the asymmetry seen in 1, with mean values of 1.550 and 1.370 Å, respectively. The shape of the BOPYPY ring system of the 4c molecule is like that of 1, except that the central C₂BN₃ ring in this case is nonplanar, with the B atom 0.29 Å out of the plane of the other five atoms. The dihedral angles between the central ring and F₄Ph, and between the central ring and the pyrazine are 0.9° and 9.7°, respectively. The N–C–S–C torsion angle to the ethylthio substituent is 114.9(6)°, and the B–N and B–F distances are not asymmetric, with average values of 1.574 and 1.364 Å, respectively. The C–S distance from the ring system to the S atom is 1.752(6) Å. The crystal structure of 4e is unusual in that there are 13 molecules in the asymmetric unit. The largest differences among them are the different conformation of the ethyl groups of the diethylamine substituent. In a typical molecule, the central C₂BN₃ ring is nearly planar, with average deviation of 0.05 Å. The 5-ring system is closer to planarity than the previously described molecules, with the F₄Ph group forming a dihedral angle of 3.7° with the central ring and the pyrazine forming a dihedral angle of 5.4°. Although the precision is not high for this structure, there does not appear to be any difference between the B–N and B–F distances for the two boron atoms.

Figure 3.

X-ray crystal structures of BOPYPYs 4a, 4c, 4d, and 4e with 50% ellipsoids.

The regioselectivity of fluoride substitution on select BOPYPYs 4d, 4e, and 4g was then investigated in the presence of the most reactive 4-methoxythiophenol, as shown in Scheme 4. When BOPYPYs 4d, 4e, and 4g were reacted with a slight excess of the nucleophile at room temperature in dichloromethane solution, the corresponding BOPYPYs 5a, 5b, and 5c were isolated in 72, 92, and 84% yields, respectively. These BOPYPYs could also be prepared from 3 by first performing α-bromination followed by nucleophilic substitution using the appropriate nucleophile, albeit in lower overall yield. The structures of BOPYPYs 5a, 5b, and 5c were investigated using ¹⁹F, ¹¹B, ¹H NMR spectroscopy and 2D ¹H–¹⁹F HOESY (see Figures S31–S39, S50 and S51), HRMS (Figures S78–S80), and by X-ray crystallography, as shown in Figure 4. As expected, as previously observed with a tetrafluorobenzo-[α]-fused BOPHY,¹⁹ the nucleophilic substitution occurs regioselectivity at the F² position. These results are supported by the calculated MESP reactivity descriptors, which indicate that the F² site is the most reactive toward nucleophilic substitution, except in the case of 4e. Indeed, the performed calculations for compounds 4b, 4d, 4e, and 4g (see Figure S64) indicate that the α-substituent on BOPYPY 4 influences the values of the carbon MESPs. Interestingly, the effect is more pronounced on the bis-BF₂ and pyrazine moieties; however, the tetrafluoro aromatic carbon MESPs also change upon α-substitution. In the case of 4e, the F⁴ site bears the least negative MESP, but the proximity of the diethylamine group and its involvement in a hydrogen bonding interaction with F⁴ (Figure S64) reduce the reactivity at this site, making the F² position the most favored site for reaction, in agreement with the experimental findings. It is also worth noting that our calculations indicate that the N-substituents tend to increase the regioselectivity for F² substitution compared to the S-substituents.

Scheme 4. Regioselective S_NAr Reactions on Select BOPYPYs 4.

Figure 4.

X-ray crystal structures of disubstituted BOPYPYs 5a, 5b, 5c, and 7 with 50% ellipsoids.

As shown in Figure 4, the central C₂BN₃ ring in 5a is slightly nonplanar, with the boron atom lying 0.25 Å out of the plane of the other five atoms. The fluorinated phenyl group is almost coplanar with it, forming a dihedral angle of 1.4°. The pyrazine ring is tilted by 8.7° from the central ring. In 5b, the BOPYPY ring system is similar to that in 4e, not deviating much from coplanarity. The central 6-membered ring has a mean deviation 0.07 Å, the phenyl ring forms a dihedral angle of 1.7° with it, and the pyrazine forms a dihedral angle of 5.7° with it. The B–N and B–F distances do not differ between the two boron atoms, and the C–S distance to the ring system is 1.775(3) Å. The precision of the structure determination of 5c is lower, but it shows that the BOPYPY ring system is bowed. The central C₂BN₃ ring has a dihedral angle of 8.7° with the phenyl ring and a dihedral angle of 12.2° with the pyrazine ring. The dihedral angle between the BOPYPY core and the dimethylpyrrole substituent is 45.6°, and the N–H group forms an intramolecular hydrogen bond with the neighboring BF₂ fluorine atom, having a N···F distance of 2.904 Å.

Interestingly, different regioselectivity resulted when BOPYPY 4b reacted with 4-methoxythiophenol at room temperature, as shown in Scheme 5. In this case, F⁴ was substituted instead, giving BOPYPY 6 as the only product, isolated in 97% yield. Similar results were also obtained when BOPYPY 2 was treated with an excess (3 equiv) of 4-methoxythiophenol; in this case, 6 was obtained in slightly lower yield (Scheme 5). A possible explanation for the observed regioselective substitution of F⁴ are the stabilizing π–π stacking interactions between the 4-methoxythiophenol molecules, which place the nucleophile in 4b in very close proximity to F⁴ leading to its substitution, rather than at the more electronically favored F². Indeed, we have observed similar regioselectively in the multisubstitution of a tetrafluorobenzo-[α]-fused BODIPY using an aromatic thiophenol as the nucleophile.²⁰ Although the calculated MESPs for BOPYPY 4b indicate that the F² site is the most susceptible to nucleophilic substitution, compound 6 was found to be the most stable product among all possible regioisomers using the ωB97X-D DFT potential (Figures S64 and S65).²⁷ Since the ωB97X-D method accounts for dispersion interactions, this result is in agreement with the hypothesized stabilizing π–π stacking interactions that lead to the formation of BOPYPY 6.

Scheme 5. Regioselective S_NAr Reactions with Different Regioselectivity.

The structure of BOPYPY 6 was further confirmed by ¹⁹F, ¹¹B, ¹H NMR and 2D ¹H–¹⁹F HOESY spectroscopy (see Figures S40–S42 and S53). In the ¹⁹F NMR spectrum of 6, the three fluorine atoms produced distinct signals at −115.23 (F¹), −145.01 (F²), and −134.57 (F³) ppm; a cross-peak was observed in 2D ¹H–¹⁹F HOESY between the meso-hydrogen at 8.18 ppm and the F¹ atom of BOPYPY 6, showing that the 4-methoxythiophenol group regioselectively replaced F⁴.

2.3. Stille Coupling Reaction

The Stille cross-coupling reaction is an attractive methodology for the introduction of a variety of substituents under mild conditions onto halogenated BODIPYs and their derivatives.^26,28 BOPYPY 2 reacted with an excess of 2-(tributylstannyl)thiophene in the presence of 5 mol % of chloro(tricyclohexylphosphine-2–2’aminobiphenyl) palladium [Pd(PCy₃)G₂] as the catalyst, giving BOPYPY 7 in 53% yield (Scheme 6). The structure of 7 was confirmed by¹⁹F, ¹¹B, ¹H NMR spectroscopy (see Figures S43–S45), HRMS (Figure S82), and X-ray crystallography, confirming the regioselectivity of the reaction. In BOPYPY 7 (Figure 4), the 20-atom main ring system of is nearly planar, with mean deviation of only 0.034 Å. The thiophene plane makes a dihedral angle of 56.5° with it, and the B–N and B–F bond distances are like those of 4a.

Scheme 6. Regioselective Stille Cross-Coupling Reaction of BOPYPY 2.

2.4. Spectroscopic Properties

The spectroscopic properties of the new fluorinated BOPYPYs were evaluated in dichloromethane and toluene solutions. The results obtained from these studies are summarized in Table 2, and the spectra are shown in the Figures S56–S62. For comparison purposes, the previously reported BOPYPY 8¹⁶ and BOPPY 9(15,17) (see Figure 5) were synthesized, and their spectroscopic properties evaluated under the same conditions.

Table 2. Spectroscopic Properties of BOPYPYs at Room Temperature, in Both CH₂Cl₂ and Toluene Solutions.

	dichloromethane		toluene
BOPYPY	λabsmax/nm (log ε)	λemmax /nm (Φf, %)a	λabsmax/nm (log ε)	λemmax /nm (Φf, %)a
1	457(4.25), 474(4.24)	523, 545(6.08)	459(4.22), 486(4.20)	522, 548(18.1)
3	462(4.61), 485(4.66)	553, 570(2.83)	475(4.50), 503(4.54)	540, 568(13.3)
4a	467(4.73), 484(4.72)	567, 614(0.84)	474(4.61), 489(4.59)	552, 584(3.75)
4b	472(4.52), 493(4.57)	576, 606(0.48)	481(4.51), 509(4.54)	562, 605(3.60)
4c	471s(4.53), 485(4.57)	556, 600s(2.54)	472s(4.48), 496(4.53)	554, 602(8.77)
4d	485(4.64), 471(4.60)	552, 612s(1.18)	470(4.56), 494(4.62)	559, 607(2.51)
4e	496(4.55), 518s(4.50)	-	500s(4.50), 526(4.40)	618, 673(0.23)
4f	537(4.30), 553(4.31)	562, 600s(1.24)	541(4.25), 566(4.28)	550, 598(5.08)
4g	518(4.16), 551(4.06)	546, 596s(2.38)	532(4.19), 563(4.23)	526, 565(6.71)
5a	488s(4.13), 517(4.21)	570, 613(0.53)	489s(4.11), 524(4.24)	567, 620(1.99)
5b	511(4.54), 537(4.48)	-	527(4.43), 553(4.35)	540, 628(0.31)
5c	538(4.27), 559(4.29)	565(0.24)	549(4.26), 574(4.28)	544, 583(3.56)
6	483s(4.54), 507(4.65)	589, 631s(0.46)	488s(4.44), 512(4.52)	570, 619(3.23)
7	478 (4.57)	560, 605s(1.70)	498(4.53), 519 (4.44)	563, 603(5.52)
8b	443(4.45), 468s(4.29)	528, 556(1.14)	440(4.50), 461s(4.41)	555, 520(2.74)
9c	410(4.62), 430(4.59)	461, 485(77.0)	413(4.60), 436(4.58)	460, 481(79.1)

^aFluorescence quantum yields (Φ_f) determined using rhodamine 6G in methanol (Φ = 0.86) as standard.

^bReported fluorescence quantum yield in dichloromethane is Φ_f = 0.57.

^cReported fluorescence quantum yield in dichloromethane is Φf = 0.57.

Figure 5.

Chemical structures of previously reported BOPYPY 8(16) and BOPPY 9.¹⁵

As expected, BOPYPY 1 showed dual absorptions in both solvents with maximum absorption peaks at 457 and 474 nm in dichloromethane, which are 6–14 nm red-shifted from those of previously reported compound 8. Larger red shifts of up to 110 nm were observed for the α-substituted BOPYPYs, as previously observed, due to the extension of the π-conjugation system of the chromophore. The larger red shift observed for BOPYPYs 4f and 5c is due to their smaller HOMO–LUMO gaps, as shown by DFT calculations (Table S1). The observed red shift is influenced by the smaller dihedral angle between the pyrrolic substituent and the BOPYPY core compared with 7, as a result of hydrogen bonding between the pyrrolic NH and the adjacent BF₂ group (see Figure 4). The split absorption bands of the BOPYPYs in both solvents are likely due to vibronic progressions of the same excited state, as previously suggested.¹⁵ Indeed, in agreement with these previous studies, our DFT calculations confirm a significant shortening of the N–N bond length upon excitation (see Table S1), varying from 0.032 to 0.058 Å. This is consistent with the more N–N antibonding character of the HOMO compared to the LUMO (see Figure 6). The strengthening of the N–N bond length in the current series of BOPYPYs is accompanied by weakening of the adjacent B–N bond lengths in both the 5-membered and the 6-membered rings and corresponding shortening of the neighboring B–N bond length. The vibronic progression explanation is consistent with the experimentally observed difference in the absorption and emission spectra in both dichloromethane and toluene. The increased interactions that occur in the more polar solvent result in smearing of the double peaks and the appearance of shoulders for several of the BOPYPYs, while the peaks are sharper and the split bands more easily observable in nonpolar toluene.

Figure 6.

Frontier MO diagram for BOPYPY 1. Energies in eV. Calculated at the TD-DFT M06-2X/6-31+G(d,p) level in dichloromethane.

BOPYPY 1 shows a broad emission in dichloromethane with a maximum wavelength at 545 nm, red-shifted by about 23 nm relative to that previously reported for compound 8.¹⁶ However, the fluorescence quantum yields of BOPYPY 8 in both solvents are very low, in contrast with the previously reported values.¹⁶ Indeed, the replacement of the pyridine ring of BOPPY with a pyrazine ring in BOPYPY results in large red shifts in the wavelengths of absorption and emission and also has a dramatic effect on the fluorescence quantum yields of the compounds. To further investigate these observations, we performed TD-DFT calculations of the ground and the excited states of the entire series of compounds and analyzed their molecular orbitals. For all studied compounds, the leading transition is between HOMO and LUMO. The experimentally observed red shifts in the absorption and emission wavelengths are due to stabilization of both HOMO and LUMO, with significantly greater effect on LUMO (Table S1). This results in a significantly smaller HOMO–LUMO gap in BOPYPY 8 compared to BOPPY 9 and therefore explains the observed red shift. One major difference between the electronic structure of the pyridine ring in BOPPYs and the pyrazine ring in BOPYPYs is the existence of the pyrazine N-lone pair MO that is absent in pyridine. This MO is present in the entire series of BOPYPYs studied. For example, Figure 6 shows the molecular orbital diagram in the case of BOPYPY 1. The pyrazine N-lone pair molecular orbital appears as HOMO–4 and is localized mainly on the pyrazine. Just a small part of the 6-membered BF₂ ring contributes to this MO, leaving the majority of the BOPYPY core with little to no electron density, resulting in a charge-transfer quenching of the fluorescence. Our TD-DFT calculations show that this charge-transfer transition occurs between HOMO–4 and LUMO and LUMO+1 and corresponds to excitation to S₃. We hypothesize that the lower observed fluorescence in BOPYPYs compared to BOPPYs is the result of an internal conversion from S₁ to the optically dark state (S₃, in the case of BOPYPY 1). This is in agreement with previously published detailed experimental and theoretical study of pyrazine,²⁹ suggesting an internal conversion process involving a similar dark state. To further investigate this hypothesis, we performed TD-DFT calculations of the first 10 excited states for compounds 1, and 3–9. We found that similar charge-transfer transitions between the pyrazine N-lone pair molecular orbital and LUMO and LUMO+1 are observed for the entire series of BOPYPYs studied. As shown in Figure S67, the dark excited state appears as S₃, S₄, or S₅, depending on the BOPYPY substituent(s). Such an excited state does not exist in the case BOPPY 9. As expected, the energy of the dark excited state is relatively independent of the substituent on the isoindole moiety because the electron density is localized mainly on the pyrazine ring. For all BOPYPY compounds studied (1, 3–8), we observed the existence of multiple excited states that are very close in energy, thus supporting the internal conversion hypothesis. The substituted BOPYPYs 3, 4, and 5 derivatives displayed even lower fluorescence quantum yields compared with BOPYPY 1. Indeed, the substituents introduce additional excited levels that are very close in energy to the dark state, as shown in Figure S67. Our results are also in agreement with previous studies on 8-halo-BODIPYs and their 8-(C, N, O, S)-substituted analogs.³⁰

Another characteristic of BOPYPY dyes is their large Stokes shifts, in the order of ca. 3000 cm^–1. These values are larger than those reported for symmetric BODIPY systems and their derivatives, such as for aza-BODIPYs and BOPHYs.^31,32 The performed TD-DFT calculations (Table S1) also demonstrate larger Stokes shifts for unsymmetric BOPYPYs compared with symmetric BOPHYs.¹⁹ The reason for the large Stokes shifts might be the significant change in the N–N and associated B–N bond lengths upon excitation. Except for 4f, 4g, and 5c, the Stokes shifts in these compounds were similar to those observed for BOPYPY 1.

In toluene, small red shifts were observed in the absorption spectra for most of the BOPYPYs synthesized, as previously observed for BODIPY derivatives. The relative fluorescence quantum yields of the BOPYPYs also increased in the nonpolar toluene relative to dichloromethane, as previously observed in the case of BOPPY dyes,^15,17 due to the stronger interactions with the more polar solvent.

Although BOPYPYs display low fluorescence quantum yields, their strong absorptions (ε = 14300–53,700 M^–1.cm^–1) in the visible region of the optical spectrum warrant their investigation as potential optical sensors. Interestingly, we observed that upon addition of an excess of DBU (>50 equiv) to a dilute solution (ca. 10^–5 M) of each BOPYPYs caused immediate loss of color. We hypothesize that the base attacks the BOPYPYs’ electron deficient meso-position leading to disruption of conjugation, similar to that observed in the case of BOPHYs.¹⁹ Studies on the potential application of these BOPYPYs as base sensors are currently underway in our laboratory.

3. Conclusions

We report the synthesis of a new series of fluorinated benzo-[α]-fused BOPYPY dyes with extended π-conjugated systems from those previously reported. These unsymmetric bisBF₂ compounds display nearly planar or slightly bowed structures, with the two BF₂ moieties having distinct coordination geometries in a 6- or 5-membered ring. The reactivity of α-bromo-BOPYPY 2 was investigated in nucleophilic substitutions with N-, O-, S-, and C-centered nucleophiles, and in a Pd(0)-catalyzed Stille cross-coupling reaction. The regioselectivity of nucleophilic substitution reactions at the aromatic fluorine atoms was investigated on the α-free BOPYPY 1 and on the α-substituted BOPYPYs 4b, 4d, 4e, and 4g. With the exception of 4b, the F² position is electronically and/or sterically favored, giving the corresponding product with high regioselectivity. In the case of BOPYPY 4b, the F⁴ is the favored substitution site due to stabilizing π–π-interactions between the two aromatic groups.

The new BOPYPYs show dual absorptions due to vibronic progressions in the same excited state, as suggested by DFT calculations, and 6–55 nm red-shifted from those of previously reported compounds. They also show broad emissions and large Stokes shifts, in the order of 3000 cm^–1, which are attributed to changes in the N–N and associated B–N bond lengths upon excitation. The relative fluorescence quantum yields of the BOPYPYs are lower than those observed for the related BOPPYs because of an internal conversion transition to a dark excited state due to the presence of the pyrazine N-lone pair molecular orbital. Our results show for the first time the drastic effect of presence of the N-lone pair on the pyrazine ring of BOPYPYs on the fluorescence properties of this type of dye. Nevertheless, BOPYPYs might find applications as optical sensors, for example for bases such as DBU.

4. Experimental Section

4.1. General

All reagents and solvents were purchased from commercial vendors and used as received without further purification, unless otherwise stated. Reactions were conducted in oven-dried glassware and monitored by plastic backed thin-layer chromatography plates. The plates were viewed by 254/365 nm UV indicator. Purification of the compounds was performed on silica backed preparative TLC plates from Sorbtech or by silica gel column chromatography (60 Å, 40–63 μm). All NMR spectra were recorded using a Bruker spectrometer operating at 400 MHz for ¹H, 128 MHz for ¹¹B, and 376 MHz for ¹⁹F. Chemical shifts (δ) are given in ppm relative to CDCl₃ (7.26 ppm for ¹H), acetone-d₆ (2.05 ppm for ¹H), CF₃COOH in CDCl₃ (−76.6 ppm for ¹⁹F), and BF₃•OEt₂ in CDCl₃ (0.00 ppm for ¹¹B). Coupling constants (J) are reported in Hz. Peak multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), td (triplet of doublets), and m (multiplet). High-resolution mass spectra (HRMS) data were obtained at the LSU Mass Spectrometry Facility (MSF) using an Agilent 6230 ESI TOF, Waters Synapt XS and Bruker rapifleX MALDI TOF/TOF. 4,5,6,7-Tetrafluoroisoindole was prepared following a previously reported procedure, and the characterization data were in agreement with reported data.¹⁸ BOPYPYs 8(16) and 9(15) were also prepared according to the published procedure. While the spectroscopic data agree with that previously published for 9, it is not in agreement with the data published for 8. For BODIPY 8: ¹H NMR (400 MHz, CDCl₃) δ9.06 (s, 1H), 8.12 (d, J = 3.8 Hz, 1H), 7.73–7.68 (m, 2H), 6.20 (s, 1H), 2.51 (s, 3H), 2.32 (s, 3H). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₁₁H₁₂B₂F₄N₅, 312.1215; found 312.1222. X-ray structures were obtained for both 8 and 9, as shown in the Figures S53 and S54. Caution: the synthetic procedures use flammable organic solvents (acetone, chloroform, dichloromethane, toluene, ethyl acetate, and hexane) both as reaction solvents and for purification of the products.

4.2. Synthesis and Characterization

4.2.1. BOPYPY 1

p-Toluenesulfonic acid (4.76 mg, 0.028 mmol) was added to 4,5,6,7-tetrafluorobenzo[c]pyrrole-1-carbaldehyde (200 mg, 0.921 mmol) and 2-hydrazinopyrazine (111.6 mg, 1.01 mmol) in 1,2-dichloroethane (25 mL). The reaction mixture was left refluxing for 6 h. Upon complete disappearance of the starting material, 1.30 mL of DBU was added and the reaction left stirring for 10 min before slowly adding 1.20 mL of BF₃•OEt₂. The reaction mixture was further heated under reflux for 1 h, then cooled to room temperature before adding sat. NaHCO₃ (50 mL) then extracting three times with CH₂Cl₂ (50 mL). The organic layers were combined, washed with water, dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/n-hexane (1:6) to afford 1 (114 mg, 31%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 8.36–8.29 (m, 2H), 8.26 (s, 1H), 7.86 (dd, J = 3.8, 1.6 Hz, 1H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.62–2.59 (m), 1.02 (t, J = 28.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −141.53 (dd, J = 56.1, 27.8 Hz, 2F), −144.31 (td, J = 18.7, 3.5 Hz, 1F), −144.40 (m, 2F) −147.83 (t, J = 19.3 Hz, 1F), −152.76 (td, J = 18.4, 3.5 Hz, 1F), −160.06 (t, J = 18.3 Hz, 1F). HRMS (ESI-TOF) m/z [M]⁻ calcd for C₁₃H₅B₂F₈N₅, 405.0613; found 405.0649.

4.2.2. BOPYPY 2

Bromine liquid (157.9 μL, 0.988 mmol) was added dropwise to a stirring solution of BOPYPY 1 (100 mg, 0.247 mmol) in 50 mL of CHCl₃ at 40 °C. After 12 h of stirring, the reaction was quenched with 50 mL of sat. Na₂S₂O₃ solution, followed by extraction with CH₂Cl₂. The organic layers were combined, dried over anhydrous Na₂SO₄, and evaporated to dryness. The crude solid was recrystallized from hexane/dichloromethane to afford 2 (118 mg, 0.244 mmol) as an orange powder in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.33 (d, J = 3.7 Hz, 1H), 8.17 (s, 1H), 7.86 (dd, J = 3.8, 1.6 Hz, 1H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.03 (t, J = 23.7 Hz), 0.98 (t, J = 28.2 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −138.06 (dd, J = 56.3, 28.1 Hz, 2F), −144.12 to −144.48 (m, 2F), −147.72 (t, J = 19.1 Hz, 1F), −148.23 (td, J = 18.7, 4.1 Hz, 1F), −151.31 (td, J = 18.5, 4.1 Hz, 1F), −158.80 (t, J = 18.2 Hz, 1F). HRMS (ESI-TOF) m/z [M]⁻ calcd for C₁₃H₄B₂BrF₈N₅, 482.9721; found 482.9725.

4.2.3. BOPYPY 3

One drop of NEt₃ was added to a stirring solution of BOPYPY 1 (18 mg, 0.044 mmol) and 4-methoxythiophenol (12 μL, 0.098 mmol) in 3 mL of dichloromethane. The reaction mixture was left stirring at room temperature for 12 h after which the solvent was removed under reduced pressure, and the residue purified by column chromatography on silica gel using ethyl acetate/hexane 1/5 as eluent. Compound 3 (15.8 mg, 0.030 mmol) was collected as an orange powder in 68% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.30 (d, J = 3.7 Hz, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 7.84 (dd, J = 3.8, 1.6 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 2.98, 1.04 (t, J = 28.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −114.66 (d, J = 21.0 Hz, 1F), −135.30 (d, J = 20.3 Hz, 1F), −140.37 (dd, J = 56.3, 27.7 Hz, 2F), −143.44 (d, J = 31.2 Hz, 2F), −145.84 (t, J = 20.6 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₀H₁₃B₂F₇N₅OS, 526.0929; found 526.0829.

4.2.4. BOPYPY 4a

One drop of NEt₃ was added to a stirring solution of BOPYPY 2 (15 mg, 0.031 mmol) and 4-methoxyphenol (11.6 mg, 0.093 mmol) in 3 mL of toluene. The solution was left stirring at 80 °C. for 3 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/6 as eluent. Compound 4a (8.8 mg, 0.017 mmol) was obtained as an orange powder in 54% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.22 (d, J = 3.8 Hz, 1H), 8.11 (s, 1H), 7.80 (dd, J = 4.0, 1.6 Hz, 1H), 7.07–7.01 (m, 2H), 6.92–6.85 (m, 2H), 3.81 (s, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.42–2.65 (m), 0.80 (t, J = 28.0 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −138.83 (td, J = 19.5, 5.0 Hz, 1F), −140.94 (dd, J = 55.0, 26.7 Hz, 2F), −143.68 to −143.96 (m, 2F), −147.36 (t, J = 19.2 Hz, 1F), −150.84 (td, J = 18.9, 5.0 Hz, 1F), −159.95 (t, J = 19.4 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₀H₁₂B₂F₈N₅O₂, 528.1049; found 528.1050.

4.2.5. BOPYPY 4b

One drop of NEt₃ was added to a stirring solution of BOPYPY 2 (15 mg, 0.031 mmol) and 4-methoxythiophenol (4.19 μL, 0.034 mmol) in 3 mL of chloroform. The solution was left stirring at room temperature for 1 h. The reaction solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/5 as eluent. Compound 4b (13.2 mg, 0.024 mmol) was collected as an orange powder in 78% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 1H), 8.31 (d, J = 3.8 Hz, 1H), 8.18 (s, 1H), 7.85 (dd, J = 3.8, 1.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 3.78 (s, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.56–2.54 (m), 1.29 (t, J = 28.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −135.43 (dd, J = 56.8, 27.1 Hz, 2F), −143.09 (td, J = 19.2, 4.4 Hz, 1F), −144.13 to −144.52 (m, 2F), −148.17 (t, J = 19.5 Hz, 1F), −152.75 (td, J = 19.0, 4.3 Hz, 1F), −159.45 (t, J = 18.8 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₀H₁₂B₂F₈N₅OS, 544.0821; found 544.0815.

4.2.6. BOPYPY 4c

One drop of NEt₃ was added to a stirring solution of BOPYPY 2 (10 mg, 0.021 mmol) and 4-methylbenzenethiol (3.85 mg, 0.031 mmol) in 3 mL of chloroform. The solution was left stirring at 50 °C for 1 h, and the reaction solvent was removed under reduced pressure; the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/5 as eluent. Compound 4c (8.4 mg, 0.016 mmol) was collected as an orange powder in 77% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 8.31 (d, I = 3.8 Hz, 1H), 8.19 (s, 1H), 7.85 (dd, J = 3.9, 1.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.55–2.53 (m), 1.28 (t, J = 28.2 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −135.72 (dd, J = 56.6, 26.8 Hz, 2F), −143.47 (td, J = 19.2, 4.4 Hz, 1F), −144.20 to −144.52 (m, 2F), −148.16 (t, J = 19.5 Hz, 1F), −152.72 (td, J = 19.0, 4.3 Hz, 1F), −159.33 (t, J = 18.7 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₀H₁₂B₂F₈N₅S, 528.0872; found 528.0864.

4.2.7. BOPYPY 4d

One drop of NEt₃ was added to a stirring solution of BOPYPY 2 (15 mg, 0.031 mmol) and ethanethiol (3.44 μL, 0.047 mmol) in 3 mL of chloroform. The solution was left stirring at 50 °C for 3 h. The solvent was removed under reduced pressure, and the residue purified by column chromatography on silica gel using ethyl acetate/hexane 1/6 as eluent. Compound 4d (11.9 mg, 0.026 mmol) was collected as an orange powder in 83% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 8.30 (d, J = 3.7 Hz, 1H), 8.16 (s, 1H), 7.84 (dd, J = 3.6, 1.8 Hz, 1H), 3.19 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.59–2.48 (m), 1.15 (t, J = 28.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −136.10 (dd, J = 56.5, 27.4 Hz, 2F), −144.28 to −144.62 (m, 2F), −146.30 (td, J = 19.0, 4.3 Hz, 1F), −147.96 (t, J = 19.4 Hz, 1F), −152.89 (td, J = 18.9, 4.2 Hz, 1F), −159.70 (t, J = 18.5 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₁₅H₁₀B₂F₈N₅S, 466.0715; found 466.0717.

4.2.8. BOPYPY 4e

A solution of BOPYPY 2 (15 mg, 0.031 mmol) and HNEt₂ (4.79 μL, 0.047 mmol) in 3 mL of chloroform were left stirring at room temperature for 16 h. The reaction solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/7 as eluent. Compound 4e (13 mg, 0.027 mmol) was collected as a red powder in 88% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 8.07 (d, J = 3.8 Hz, 1H), 7.89 (s, 1H), 7.72 (dd, J = 3.9, 1.6 Hz, 1H), 3.63 (q, J = 7.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.00 (t, J = 24.9 Hz), 0.87 (t, J = 30.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −137.84 to −138.23 (m, 3F), −142.52 (dd, J = 48.5, 22.5 Hz, 2F), −146.73 (t, J = 19.2 Hz, 1F), −151.40 (td, J = 19.4, 5.6 Hz, 1F), −160.79 (t, J = 19.5 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₁₇H₁₅B₂F₈N₆, 477.1416; found 477.1424.

4.2.9. BOPYPY 4f

A solution of BOPYPY 2 (15 mg, 0.031 mmol) and 3-ethyl-2,4-dimethylpyrrole (16.5 μL, 0.124 mmol) in 3 mL of toluene were left stirring at 80 °C for 3 h. The reaction solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/4 as eluent. Compound 4f (10.3 mg, 0.020 mmol) was collected as a red powder in 63% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 8.89 (s, 1H), 8.18 (d, J = 3.8 Hz, 1H), 8.11 (s, 1H), 7.78 (dd, J = 3.8, 1.5 Hz, 1H), 2.48 (q, J = 7.4 Hz, 2H), 2.35 (s, 3H), 2.07 (d, J = 4.3 Hz, 3H), 1.15 (t, J = 7.5 Hz, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.59–2.53 (m), 1.20 (t, J = 31.0 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −141.74 (td, J = 18.8, 4.7 Hz, 1F), −142.35 to −143.26 (m, 1F), −144.30 to −145.73 (m, 2F), −148.58 (t, J = 19.3 Hz, 1F), −152.89 (td, J = 19.3, 5.3 Hz, 1F), −160.69 (t, J = 18.7 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₁H₁₇B₂F₈N₆, 527.1575; found 527.1573.

4.2.10. BOPYPY 4g

A solution of BOPYPY 2 (15 mg, 0.031 mmol) and 2,4-dimethylpyrrole (12.8 μL, 0.124 mmol) in 3 mL of toluene were left stirring at 80 °C for 5 h. The reaction solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/4 as eluent. Compound 4g (12.2 mg, 0.025 mmol) was collected as a brown powder in 79% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 8.92 (s, 1H), 8.21 (d, J = 3.8 Hz, 1H), 8.14 (s, 1H), 7.80 (dd, J = 3.8, 1.6 Hz, 1H), 6.00 (d, J = 2.7 Hz, 1H), 2.39 (s, 3H), 2.12 (d, J = 3.7 Hz, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.02, 1.20 (t, J = 30.7 Hz. ¹⁹F NMR (376 MHz, CDCl₃) δ −124.44 to −125.32 (m,1F), −141.51 (td, J = 18.5, 4.4 Hz, 1F), −141.69 to −142.26 (m, 1F), −143.18 to −144.59 (m, 2F), −147.55 (t, J = 19.2 Hz, 1F), −151.79 (td, J = 19.1, 5.1 Hz, 1F), −159.47 (t, J = 18.5 Hz, 1F). HRMS (ESI-TOF) m/z [M]⁺ calcd for C₁₉H₁₂B₂F₈N₆, 498.1183; found 498.1191.

4.2.11. BOPYPY 5a

One drop of NEt₃ was added to a stirring solution of BOPYPY 4d (17 mg, 0.037 mmol) and 4-methoxythiophenol (5.40 μL, 0.044 mmol) in 4 mL of dichloromethane. The reaction mixture was left stirring at room temperature for 12 h before removing the solvent under reduced pressure, and the residue was then purified by column chromatography on silica gel using ethyl acetate/hexane 1/5 as eluent. Compound 5a (12 mg, 0.021 mmol) was collected as an orange powder in 72% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 8.28 (d, J = 3.8 Hz, 1H), 8.17 (s, 1H), 7.82 (dd, J = 3.8, 1.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 3.80 (s, 3H), 3.18 (q, J = 7.4 Hz, 2H), 1.31 (t, J = 7.4 Hz, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.51–2.56 (m), 1.19 (t, J = 28.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −115.00 (d, J = 21.5 Hz, 1F), −134.65 to −135.13 (m, 3F), −143.27 to −143.66 (m, 2F), −147.79 (t, J = 20.6 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₂H₁₇B₂F₇N₅OS₂, 586.0949; found 586.0950.

4.2.12. BOPYPY 5b

One drop of NEt₃ was added to a stirring solution of BOPYPY 4e (13 mg, 0.027 mmol) and 4-methoxythiophenol (7.05 μL, 0.057 mmol) in 3 mL of dichloromethane. The reaction mixture was left stirring at room temperature for 12 h before removing the solvent under reduced pressure, and the residue was then purified by column chromatography on silica gel using ethyl acetate/hexane 1/6 as eluent. Compound 5b (14.9 mg, 0.025 mmol) was collected as a red powder in 92% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.06 (d, J = 3.8 Hz, 1H), 7.89 (s, 1H), 7.70 (dd, J = 3.9, 1.6 Hz, 1H), 7.48 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 3.80 (s, 3H), 3.61 (qd, J = 7.1, 1.3 Hz, 4H), 1.19 (t, J = 7.1 Hz, 6H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.56–2.51 (m), 0.89 (t, J = 30.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −116.03 (d, J = 20.8 Hz, 1F), −137.21 (d, J = 21.7 Hz, 1F), −138.62 to −139.01 (m, 2F), −141.39 (t, J = 21.3 Hz, 1F), −143.51 (dd, J = 46.4, 19.9 Hz, 2F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₄H₂₂B₂F₇N₆OS, 597.1650; found 597.1660.

4.2.13. BOPYPY 5c

One drop of NEt₃ was added to a stirring solution of BOPYPY 4g (12 mg, 0.024 mmol) and 4-methoxythiophenol (8.00 μL, 0.051 mmol) in 3 mL of dichloromethane. The reaction mixture was left stirring at room temperature for 12 h before removing the solvent under reduced pressure, and the residue was then purified by column chromatography on silica gel using ethyl acetate/hexane 1/5 as eluent. Compound 5c (12.5 mg, 0.020 mmol) was collected as a red powder in 84% yield. ¹H NMR (400 MHz, CDCl₃) 9.05 (s, 1H), 8.89 (s, 1H), 8.18 (d, J = 3.8 Hz, 1H), 8.14 (s, 1H), 7.78 (dd, J = 3.8, 1.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 5.99 (d, J = 2.7 Hz, 1H), 3.80 (s, 3H), 2.38 (s, 3H), 2.11 (d, J = 3.6 Hz, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.59–2.63 (m), 1.22 (t, J = 31.1 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −115.65 (d, J = 20.7 Hz, 1F), −124.18 to −125.10 (m, 1F), −135.37 (d, J = 20.0 Hz, 1F), −141.52 to −142.28 (m, 1F), −143.52 to −144.44 (m, 2F), −144.19 (td, J = 20.4, 3.7 Hz, 1F). MALDI TOF/TOF m/z [M]⁺ calcd for C₂₆H₁₉B₂F₇N₆OS, 618.1419; found 618.1415.

4.2.14. BOPYPY 6

One drop of NEt₃ was added to a stirring solution of BOPYPY 2 (15 mg, 0.031 mmol) and 4-methoxythiophenol (11 μL, 0.093 mmol) in 3 mL of dichloromethane. The solution was left stirring at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel using ethyl acetate/hexane 1/4 as eluent. Compound 6 (16 mg, 0.024 mmol) was collected as an orange powder in 78% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.21 (s, 1H), 8.29 (d, J = 3.8 Hz, 1H), 8.18 (s, 1H), 7.83 (dd, J = 3.8, 1.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 6.84–6.80 (m, 4H), 3.78 (s, 3H), 3.77 (s, 3H). ¹¹B NMR (128 MHz, CDCl₃) δ 3.61–2.34 (m), 1.31 (t, J = 28.6 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ −115.23 (d, J = 21.4, 1.6 Hz, 1F), −134.17 (dd, J = 56.2, 26.3 Hz, 2F), −134.57 (d, J = 20.2, 1.5 Hz, 1F), −143.26 to −143.61 (m, 2F), −145.01 (t, J = 20.8 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₂₇H₁₉B₂F₇N₅O₂S₂, 664.1049; found 664.1018.

4.2.15. BOPYPY 7

Compound 2 (15 mg, 0.031 mmol), tributyl(thiophen-2-yl)stannane (19.7 μL, 0.062 mmol), and 3% mol Pd(PCy3)G2 (0.886 mg, 0.002 mmol) were combined in a flask. The flask was evacuated and refilled with nitrogen three times. Dry toluene (5 mL) was added and the reaction mixture stirred at 85 °C for 5 h under N₂. Toluene was removed under reduced pressure, and the resulting crude product was purified by column chromatography using ethyl acetate/hexane 1/5 as eluent. BOPYPY 7 was collected as an orange powder in 53% yield (8.1 mg, 0.017 mmol). ¹H NMR (400 MHz, d₆-acetone) δ 8.98 (s, 1H), 8.66 (s, 1H), 8.47 (d, J = 3.8 Hz, 1H), 8.33 (dd, J = 3.8, 1.6 Hz, 1H), 7.90 (dd, J = 5.0, 1.2 Hz, 1H), 7.71–7.66 (m, 1H), 7.30 (dd, J = 5.1, 3.7 Hz, 1H). ¹¹B NMR (128 MHz, d₆-acetone) δ 3.08 (t, J = 23.4 Hz), 1.31 (t, J = 28.9 Hz). ¹⁹F NMR (376 MHz, d₆-acetone) δ −134.30 (dd, J = 58.1, 28.9 Hz, 2F), −145.28 to −145.65 (m, 3F), −149.26 (t, J = 19.1 Hz, 1F), −157.31 (td, J = 18.2, 3.6 Hz, 1F), −163.36 (t, J = 18.1 Hz, 1F). HRMS (ESI-TOF) m/z [M + H]⁺ calcd for C₁₇H₈B₂F₈N₅S, 488.0565; found 488.0572.

4.3. X-ray Analyses

Data for compounds 1, 2, 4a, 4c, 4e, 5a, and 5b were collected on a Bruker Kappa ApexII DUO diffractometer, while those for 4d, 5c, 7, 8, and 9 were collected on a Bruker D8 Venture DUO Photon III diffractometer. Compound 5b used MoKα radiation, 7–9 used AgKα, and all others used CuKα. All data were collected at 100 K except for 9 at 296 K because of a phase change at low temperature. Crystals of 4c and 5a were twinned. 4d and 8 had two independent molecules, while 4e had 13. Compound 5b contained a small amount of a chlorinated impurity, while 2 and 7 contained small amounts of brominated impurities.

4.4. Spectroscopic Analyses

UV–vis absorption and emission spectra were collected at room temperature on a Varian Cary 50 spectrophotometer or on a PerkinElmer LS55 spectrophotometer, respectively. Dilute solutions (1.0 × 10^–6 to 5.0 × 10^–6 M) using spectrophotometric grade solvents in quartz cuvettes (1 cm path length) were used to minimize reabsorption effects. The relative fluorescence quantum yields (Φ_F) were calculated using rhodamine 6G (Φ_F = 0.86 in MeOH) as reference using the following equation:³³ Φ_X = Φ_ST × Grad_X/Grad_ST × (η_X/η_ST)², where the Φ_X and Φ_ST are the quantum yields of the sample and standard, Grad_X and Grad_ST are the gradients from the plot of integrated fluorescence intensity vs absorbance, and η represents the refractive index of the solvent.

4.5. Theoretical Calculations

All structures were optimized without symmetry constrains, and the stationary points were confirmed with frequency calculations. Solvent effects were taken into account using the polarized continuum model (PCM).³⁴ The reported energies, atomic charges, and molecular electrostatic potentials were evaluated at the ωB97X-D/6-311++G(d,p) level to include empirical dispersion.²⁷ The atomic charges were calculated using the NPA³⁵ and MK schemes.³⁶ The UV–vis absorption data were calculated using the TD-DFT method³⁷ at the M06-2X/6-31+G(d,p) level³⁸ as recommended in the literature.^39,40 All calculations were performed using the Gaussian 09 program package.⁴¹

Glossary

Abbreviations

PTSA

p-toluenesulfonic acid

DBU

1,8 diazabicyclo[5.4.0]undec-7-ene

TD-DFT

time-dependent density-functional theory

HOESY

heteronuclear overhauser effect spectroscopy

NMR

nuclear magnetic resonance

TLC

thin layer chromatography

HRMS

high resolution mass spectrometry

MESPs

molecular electrostatic potentials

NPA

natural population analysis

HOMO

highest occupied molecular orbital

LUMO

lowest unoccupied molecular orbital

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.inorgchem.4c00499.

• 1D and 2D NMR data (PDF) for all BOPYPYs, absorption and emission spectra (PDF), and X-ray data (CIF). The Supporting Information is available free of charge. CIFs for 1, 2, 4a, 4c, 4e, 5b, and 5c have been deposited at the Cambridge Crystallographic Data Center with deposition numbers CCDC 2309699–2309705. CIFs for 5a, 4d, and 7 have been deposited as CCDC 2324980–2324982. CIFs for 8 and 9 have been deposited as CCDC 2325327–2325328 (PDF)

Author Contributions

^§ S.A.H. and M.A.H. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

This research was supported by the National Science Foundation, grant number CHE-2055190.

The authors declare no competing financial interest.