Functionalized Aza-BODIPYs and Their Use in the Synthesis of Aza-BODIPY-Based Complex Systems

Abstract

In this account, we present syntheses of various functionalized aza-boron-dipyrromethene dyes (aza-BODIPYs) in which the functional groups are directly introduced at the 2- or 6-positions of the aza-BODIPYs or on aryl rings present at the 1-, 3-, 5-, and 7-positions of the aza-BODIPYs. Some of these functionalized aza-BODIPYs have been used for the synthesis of aza-BODIPY-based energy-transfer cassettes and light-harvesting complexes.

1 Introduction

2 Monofunctionalized Aza-BODIPYs

2.1 2-/6-Monofunctionalized Aza-BODIPYs

2.2 1-/3-/5-/7-Monofunctionalized Aza-BODIPYs

3 Difunctionalized Aza-BODIPYs.

3.1 2,6-Difunctionalized Aza-BODIPYs

3.2 3,5-Difunctionalized Aza-BODIPYs

3.3 1,7-Difunctionalized Aza-BODIPYs

4 Miscellaneous

5 Conclusion

Biographical Sketches

Bharti Yadav was born in India in 1994. She received her B.Sc. and M.Sc. degrees from Delhi University, Delhi. She joined the Indian Institute of Technology Bombay under the supervision of Professor M. Ravikanth in 2019. She is currently working on polyaromatic hydrocarbon-embedded porphyrinoids.

Mangalampalli Ravikanth was born in India in 1966. He received his B.Sc. and M.Sc. degrees from Osmania University, Hyderabad, and his Ph.D. from the Indian Institute of Technology, Kanpur, in 1994. After postdoctoral stays in the USA and Japan, he joined the chemistry faculty of the Indian Institute of Technology Bombay in 1999, where he is currently a full professor. His current research interests include the syntheses of porphyrinoids, pyrrole-based ligands for coordination chemistry, BODIPYs, and aza-BODIPYs.

Introduction

Boron difluoride complexes of dipyrromethenes, popularly known as BODIPYs I (Figure [1]), are versatile fluorescent dyes with a wide range of applications in various fields, ranging from materials and biology to medicine.[1] [2] [3] BODIPYs absorb and emit in the visible region with narrow absorption and emission bands, high molar-absorption coefficients, and moderate to high quantum yields, depending on the substituents present on the pyrrole rings.[4,5] The chemistry of BODIPYs has grown exponentially in the last decade because of their straightforward simple synthesis routes and their attractive photophysical properties.[6] The photophysical properties of BODIPYs can be fine-tuned by suitable modification, and some appropriately modified BODIPYs can absorb and emit in the visible/near-infrared (NIR) region with high quantum yields.[7]

Over the years, several functionalized BODIPYs in which functional groups have been introduced at all six possible pyrrole carbons of the two pyrrole rings or at the meso-carbon atom which have been further derivatized for applications in various fields.[8] These functionalized BODIPYs have been used as synthons to prepare various complex BODIPY systems, the physicochemical properties and applications of which have been explored.[9] The most interesting structural analogues of BODIPYs are the aza-BODIPYs II, in which the meso-carbon of the BODIPY core is replaced by nitrogen atom.[10] The introduction of nitrogen in place of carbon at the meso-position significantly alters the electronic properties of the compounds, and aza-BODIPYs show strong absorptions and emissions in the visible and NIR region, with a strong band in the 600–800 nm region, together with high extinction coefficients and high quantum yields.[11] Studies have also shown that aza-BODIPYs or BF₂-demasked azadipyrrins are more stable than BODIPYs or the corresponding dipyrrins. Because of their stability and their attractive NIR absorption and fluorescence features, aza-BODIPYs are useful dyes for biological and medical applications, including light harvesting, bioimaging, and photodynamic therapy of cancer.[12] [13]

General synthetic routes toward meso-aryl BODIPYs 1 and 1,3,5,7-tetraaryl aza-BODIPYs 2 are presented in Scheme [1].[14] The meso-aryl BODIPYs 1 can be synthesized in two steps, whereas 1,3,5,7-tetraaryl aza-BODIPYs 2 require multistep syntheses. To synthesize BODIPYs 1, an appropriate aldehyde and pyrrole are condensed under acid-catalyzed conditions to afford a meso-aryl dipyrromethene, which is then subjected to oxidation with an oxidant such as DDQ and subsequently complexed with BF₃·OEt₂, followed by purification by column chromatography, to give BODIPYs 1.[12a] [15] In addition to this general method, several other possible routes are available for the synthesis of BODIPYs.[9]

Aza-BODIPYs 2 with aryl substituents at the 1-, 3-, 5-, and 7-positions can be synthesized in four steps. In the first step, an aryl aldehyde and acetophenone are subjected to an aldol condensation in the presence of a base in ethanol to afford a chalcone. In the second step, the chalcone reacts with nitromethane under Michael addition reaction conditions to afford a nitrochalcone. In the third step, the nitrochalcone is treated with ammonium acetate in refluxing ethanol to afford the corresponding tetraaryl azadipyrromethene, and in the last step, the azadipyrromethene is treated with BF₃·OEt₂ in the presence of a base; subsequent column chromatographic purification affords the 1,3,5,7-tetraaryl aza-BODIPY 2. Because of the nature of the synthetic procedure and the instability of certain pyrrolic intermediates, the synthesis of aza-BODIPYs is not as simple and straightforward as that of BODIPYs. Furthermore, aza-BODIPY chemistry can be extended only if suitable functionalized aza-BODIPYs analogous to functionalized BODIPYs are available. However, the synthesis of functionalized aza-BODIPYs requires several synthetic steps, stable pyrrole-based intermediates, and laborious column-chromatographic purifications.[16] A perusal of the literature reveals that the chemistry of aza-BODIPYs has not been developed to the same extent as that of BODIPYs, although aza-BODIPYs are more attractive dyes that absorb and emit in the far-red region, unlike BODIPYs.[17] The purpose of this account is to present the available synthetic routes for the synthesis of various functionalized aza-BODIPYs, together with their use in the syntheses of various substituted aza-BODIPY-based fluorescence systems; it also aims to bring the attention of researchers to less-explored synthetic functionalized aza-BODIPY dyes and their derivatives. Interestingly, if the 1-, 3-, 5-, and 7-positions of aza-BODIPYs are substituted with aryl or alkyl groups, only the 2- and 6-positions of aza-BODIPY are available for direct functionalization. In addition, functional groups can also be introduced onto the aryl groups on the 1-, 3-, 5-, and 7-positions. In this account, we systematically describe the syntheses of various functionalized aza-BODIPYs and their use in the synthesis of various aza-BODIPY-based fluorescent compounds.

Monofunctionalized Aza-BODIPYs

2-/6-Monofunctionalized Aza-BODIPYs

The 1,3,5,7-tetraaryl aza-BODIPYs 2 have two reactive β-pyrrole positions, the 2- and 6-positions, where a functional group can be introduced; the resulting functionalized aza-BODIPYs are useful for preparing novel aza-BODIPY derivatives with interesting physicochemical properties.

Interestingly, a perusal of literature revealed that monofunctionalized aza-BODIPYs are rare, and only three types of monofunctionalized aza-BODIPYs, the 2-/6-formyl aza-BODIPY 3a and 3b, the 2-/6-nitro aza-BODIPYs 4a and 4b, and the 2-/6-iodo aza-BODIPYs 4c and 4d have been reported so far (Scheme [2]). The 2-/6-formyl-1,3,5,7-tetraaryl aza-BODIPYs 3a and 3b were prepared by treating aza-BODIPYs 2a and 2b, respectively, with POCl₃ in DMF under Vilsmeier–Haack reaction conditions at 80 °C for three hours; subsequent silica gel column chromatographic purification afforded the desired products in 85% yield.[18] The reaction did not show any indication of the formation of 2,6-diformyl aza-BODIPYs, and under the stringent conditions, the reaction gave the 2-/6-monoformyl aza-BODIPY 3a and 3b, exclusively. The mono 2-/6-nitro aza-BODIPYs 4a and 4b were prepared by treating the aza-BODIPY 2c and 2d, respectively, with concentrated HNO₃ at 80 °C for 25–30 minutes; simple workup and column chromatographic purification gave the products in yields of 21–28%.[19a] The authors mention that the nitration of aza-BODIPYs requires continuous monitoring to obtain mono-β-nitro aza-BODIPYs, and that mononitration at the 2-/6-position also depends on the presence of electron-deficient aryl substituents at 1-, 3-, 5-, and 7-positions. Although the mono-2-/6-nitro aza-BODIPYs 4a and 4b have not been subjected to further derivatization, they nevertheless show an incredibly diverse range of absorption (λ_abs = ~640 nm in toluene) and emission maxima (λ_em = 690 nm in toluene) that depend on the substitution pattern of the proximal and distal rings. Furthermore, aza-BODIPYs 4a and 4b can act as effective push–pull NIR-absorbing and -emitting dyes, with quantum yields ranging from 0.14 to 0.42 in various solvents. Similarly, the mono-2-/6-iodo aza-BODIPYs 4c and 4d were prepared by treating aza-BODIPYs 2a and 2e, respectively, with N-iodosuccinimide (NIS) in CH₂Cl₂–acetic acid at room temperature for 30 minutes.[19b] The monoiodinated aza-BODIPYs 4c and 4d absorb (λ_abs = 659–678 nm) and emit (λ_em = 690–721 nm) in the NIR region with quantum yields of 0.04–0.08.

The 2-/6-monoformylated aza-BODIPYs 3a and 3b have been used as key building blocks to prepare aza-BODIPY-based conjugated systems (Scheme [3]). The 2-/6-monoformyl aza-BODIPY 3b was treated with an excess of ylides I and II in CH₂Cl₂ under Wittig reaction conditions at room temperature for one to two hours to afford the conjugated aza-BODIPYs 5a and 5b in yields of 82–85% (Scheme [3]).[20] This method, with ylide III, was also used effectively to prepare the biologically relevant aza-BODIPY–cholesterol conjugate 5c in a good yield. The aza-BODIPYs 5a–c absorb at ~666 nm and emit in the range 700–707 nm with quantum yields of 0.11–0.24.

Nemyekin and co-workers[21] also used the 2-/6-formyl aza-BODIPY 3a to synthesize the aza-BODIPY probe 6 in 21% yield, by treating it with hydroxylamine sulfate in the presence of pyridine at 60 °C for eight hours. Product 6 showed good biocompatibility and a specific sensing ability for hypochlorous acid in various biological systems. Although aza-BODIPY probe 6 was weakly fluorescent with a quantum yield of 0.0012, it showed a 7.7-times increase in fluorescence upon the addition of sodium hypochlorite solution, and the emission wavelength was red-shifted from 660 nm to 670 nm. Furthermore, the 2-/6-formyl aza-BODIPY 3b was treated with pyrrole in CH₂Cl₂ in the presence of a catalytic amount of BF₃·OEt₂ at room temperature for 15 minutes to give the dipyrromethanyl aza-BODIPY 7 in 62% yield.[18] The 2-/6-dipyrromethanyl aza-BODIPY 7 was oxidized by treatment with DDQ in CH₂Cl₂ at room temperature for two hours in the open air, with subsequent purification by silica gel column chromatography, to afford the highly stable 2-/6-dipyrrinyl aza-BODIPY 8 in 81% yield.

An X-ray structural analysis of dipyrrinyl aza-BODIPY 8 showed that the dipyrrinyl unit is oriented with a dihedral angle of 68° with respect to the aza-BODIPY unit to avoid steric congestion between the dipyrrin unit and the four aryl substituents present at the 1-, 3-, 5-, and 7-positions of the aza-BODIPY unit (Figure [2]). The absorption spectrum of 2-/6-dipyrrinyl aza-BODIPY 8 showed one strong band at 660 nm, corresponding to the aza-BODIPY moiety, and a broad band at 439 nm, corresponding to the dipyrrin unit.

The dipyrrin unit at the 2-/6-position of aza-BODIPY 8 is useful for preparing aza-BODIPY conjugates, such as the aza-BODIPY–BODIPY dyad 9a and the aza-BODIPY–metal dipyrrin conjugates 9b–e (Scheme [4]). The 2-/6-dipyrrinyl aza-BODIPY 8 was treated with BF₃·OEt₂ in CH₂Cl₂ in the presence of triethylamine at room temperature for 15 minutes, with subsequent silica gel column chromatographic purification, to afford the aza-BODIPY–BODIPY dyad 9a in 30% yield.[18] An X-ray structural analysis of 9a revealed that the aza-BODIPY and BODIPY units form an angle of 62°, indicating that they are not in the same plane (Figure [3]). Because the BODIPY unit absorbs at a higher energy (λ_abs = 508 nm in toluene) than aza-BODIPY (λ_abs = 665 nm in toluene), there is a possibility of energy transfer in the singlet state from the BODIPY unit to the aza-BODIPY unit in the directly linked aza-BODIPY–BODIPY dyad 9a. The authors carried out extensive ultrafast photophysical studies, and they identified the presence of an efficient Förster energy transfer from the BODIPY unit to the aza-BODIPY unit in dyad 9a. However, the possibility of electron transfer between the BODIPY and aza-BODIPY units in dyad 9a was not ruled out completely.

The 2-/6-dipyrrinyl aza-BODIPY 8 was also used to prepare the aza-BODIPY–metal–dipyrrin conjugates 9b–e.[5] [6] Compound 8 was treated with appropriate metal salt [Ni(acac)₂, Pd(acac)₂, Re(CO)₅Cl, or Zn(OAc)₂] in toluene under reflux conditions for two to three hours, followed by column chromatographic purification, to afford the corresponding aza-BODIPY–metal–dipyrrinyl conjugates 9b–e in yields of 42–65% (Scheme [4]).[22] The metal–dipyrrinyl conjugates 9b–e exhibited one well-defined band in the region 400–550 nm, corresponding to the metal–dipyrrinyl unit, and one strong band in the region 600–700 nm, corresponding to the aza-BODIPY unit. It is interesting to note that conjugates 9b–e are weakly fluorescent (Φ_f ≤ 0.01). An X-ray structural analysis of aza-BODIPY–Re(I) dipyrrin 9d showed that the aza-BODIPY and metal dipyrrinyl units were in a perpendicular orientation with respect to each other, whereas in the aza-BODIPY–Pd(II) dipyrrin conjugate 9b, both units were oriented at 80° with respect to each other (Figure [4]). Absorption spectral studies of 9b–e showed the presence of a strong sharp high-intensity band at ~650 nm, corresponding to the aza-BODIPY unit, and one strong band in the region 400–450 nm corresponding to the metal dipyrrinyl moiety. Redox studies showed that no metal-based oxidation or reduction was observed, and both the aza-BODIPY and BODIPY units interact weakly and retain their individual characteristic features in the aza-BODIPY–metal–dipyrrin conjugates 9b–e.

1-/3-/5-/7-Monofunctionalized Aza-BODIPYs

There are few examples of 1-/3-/5-/7-monofunctionalized aza-BODIPYs, and their syntheses involve numerous steps and laborious chromatographic purifications. Some 1-/3-functionalized aza-BODIPYs have been synthesized by the sequence of steps shown in Scheme [5].[23] To synthesize 1-/3-functionalized aza-BODIPYs, a functionalized ketone 10 or a functionalized aldehyde 11 were condensed with the appropriate nonfunctionalized arylated aldehyde 15 or ketone 14, respectively, to obtain chalcones 12 and 16, which were subjected to Michael addition with MeNO₂ at 60 °C for one to three hours to give the nitrochalcones 13 and 17; condensation of 13 and 17 with NH₄OAc in EtOH at 95 °C for five hours gave the 1-/3-functionalized azadipyrromethenes 18. These were treated with BF₃·OEt₂ in the presence of a base at room temperature for 24 hours, followed by chromatographic purification, to afford the 1-/3-functionalized aza-BODIPYs 19a–o.

The 5/7-monfunctionalized aza-BODIPYs 29a–h were synthesized similarly (Scheme [6]).[24] Here, the functionalized nitrochalcones 27 were synthesized by aldol condensation of functionalized aldehyde 25 with aryl ketone 24 at room temperature for 12 hours, followed by Michael addition. The nonfunctionalized nitrochalcones 23 were similarly synthesized in two steps. Condensation of the functionalized nitrochalcones 27 with the nonfunctionalized nitrochalcones 23 in EtOH in the presence of NH₄OAc at the reflux for 12 hours, followed by chromatographic purification, afforded the 5-/7-functionalized azadipyrromethenes 28, which were complexed with BF₃·OEt₂ in the presence of a base at room temperature for 30 minutes to afford the corresponding 5-/7-functionalized aza-BODIPYs 29a–h. Oxidation of aza-BODIPY 29e with MnO₂ gave the monoformylated derivative 30. Some of these monofunctionalized aza-BODIPYs were further derivatized and used for various applications.

The 3-functionalized aza-BODIPY 19l was treated with NaNO₂ in AcOH at 20 °C for two hours to afford N-nitrosamino-3-functionalized aza-BODIPY 31 (Scheme [7]).[25] This aza-BODIPY 31 can release the NO group and produces heat under light irradiation. This feature was used for synergetic gas therapy and photothermal therapy for therapeutic applications. Aza-BODIPY 31 absorbs at 524 nm and emits in the NIR region (λ_em = 731 nm in DMSO).

Another 3-functionalized aza-BODIPY 19k was derivatized treatment with 1-[6-(chloromethyl)-2-pyridinyl]-N,N-bis(2-pyridinylmethyl)methanamine (TPACl) in THF at 40 °C overnight in the presence of NaH/KI, followed by alumina column chromatographic purification, to afford derivative 32 (Scheme [8]).[26] Compound 32 was used to detect basal levels of Cu(I) in healthy wild-type mice, as well as elevated Cu in a Wilson’s disease model.

The 7-(p-bromophenyl)-functionalized azadipyrromethene 28a was treated with various aryl bromides under Heck coupling conditions at 100 °C for eight hours to afford the corresponding 7-functionalized azadipyrromethenes 33 with functionalized terminal alkene groups; these derivatives were then complexed with BF₃·OEt₂ under the standard conditions to afford the 7-functionalized aza-BODIPYs 34a–k in yields of ~80% (Scheme [9]).[27]

One of the 7-functionalized aza-BODIPY derivatives containing an azido functional group (34j), was treated with N-(4-ethynylphenyl)-4-methylbenzenesulfonamide in THF under click reaction conditions at 65 °C until completion to afford the fluorescent bioactive aza-BODIPY analogue 35 in 99% yield; this product was tested for biological applications (Scheme [9]).[12a] [b] [28] The aza-BODIPY derivatives 34a, 34j, and 35 absorb in the range 650–660 nm and emit at 685 nm with quantum yields in the range 0.13–0.18.

The 7-functionalized aza-BODIPY 30 containing p-formylphenyl group has been used to prepare several aza-BODIPY–chromophore conjugates (Scheme [10]). The 7-azaBODIPY 30 was treated with excess pyrrole under acid conditions at room temperature for 15 minutes to afford the 7-dipyrromethanyl aza-BODIPY 36.[24a] This was oxidized in situ by treatment with DDQ, and the resulting 7-dipyrrinyl aza-BODIPY was complexed with BF₃·OEt₂ or Pd(acac)₂ to afford the corresponding aza-BODIPY–BODIPY dyad 37a and the aza-BODIPY–Pd(II) dipyrrin conjugate 37b, respectively. Compound 36 was condensed with a dipyrromethane diketone and an oxatripyrrane under standard acid-catalyzed conditions, followed by DDQ oxidation at room temperature for two hours, to the afford aza-BODIPY–porphyrin conjugate 37c and the aza-BODIPY–oxasmaragdyrin conjugate 37d, respectively. The photophysical data for aza-BODIPYs 36 and 37a–d are listed in Table [1]. Photophysical studies indicated the possibility of an energy transfer from the energy donor to the aza-BODIPY unit, which acts as energy acceptor in the aza-BODIPY-based conjugates 37b–d.

Difunctionalized Aza-BODIPYs

2,6-Difunctionalized Aza-BODIPYs

The 2,6-positions of aza-BODIPYs can be functionalized with two similar or two different functional groups (Scheme [11]); however, there are few reports of such reactions. The 2,6-dibromo aza-BODIPY derivatives 38 were synthesized in yields of 80–85% by treating the corresponding aza-BODIPY 2 with Br₂ in benzene at the reflux for two to three hours or by treatment with 2.2 equivalents of N-bromosuccinimide in CHCl₃ at room temperature for 24 hours.[12a] [b] [28] The 2,6-diiodo aza-BODIPY derivatives 39 were synthesized by treating the corresponding aza-BODIPY 2 with N-iodosuccinimide in CHCl₃ at room temperature for 24 hours.[29] Attempts were also made to prepare the 2,6-diformyl aza-BODIPY 40 under Vilsmeier–Haack reaction conditions, but only a 2-formyl aza-BODIPY 3 was obtained. However, when the formyl aza-BODIPY 3 was treated with NBS in CHCl₃ at room temperature for one hour, it afforded a 2-bromo-6-formyl aza-BODIPY 41 in 87% yield (Scheme [16]). The 2,6-dinitro aza-BODIPYs 42 were synthesized by treating the corresponding aza-BODIPY 2 with 50% aqueous HNO₃ (v/v) at 0 °C for four hours[19] when electron-donating groups such as 4-methoxyphenyl or 4-methylphenyl were present at the 1-, 3-, 5-, and7-positions, whereas harsher conditions, such as a temperature of 80 °C and a longer reaction time, were required for the synthesis of dinitrated aza-BODIPYs having an electron-withdrawing group, such as 4-(trifluoromethyl)phenyl, at the 1-, 3-, 5-, and7-positions of the aza-BODIPY.

The 2,6-difunctionalized aza-BODIPYs were used further to introduce two identical or different substituents at the 2- and 6-positions of aza-BODIPYs. The 2,6-dibromo aza-BODIPY 38a was treated with 2-(tributylstannyl)thiophene in dry toluene in the presence of catalytic amount of Pd(PPh₃)₄ at the reflux overnight to afford the 2,6-dithienyl-1,3,5,7-tetraphenyl aza-BODIPY 43 (R¹ = R² = H) in 85% yield (Scheme [12]).[30] Recently, Sun and co-workers synthesized the NIR-II emissive BODIPY ligand 44 by reacting aza-BODIPY 38d with 4-[5-(tributylstannyl)thien-2-yl]pyridine and a catalytic amount of Pd(PPh₃)₂Cl₂ at 80 °C overnight under similar palladium coupling conditions (Scheme [12]).[31]

Ravikanth and co-workers used the 2,6-dibromo aza-BODIPY 38b to prepare the sterically crowded hexaarylated aza-BODIPYs 45a–f in yields of 25–35%, by reacting it with various arylboronic acids and Na₂CO₃ in 1:1:1 water–THF–toluene at 80 °C for six to ten hours under Suzuki coupling reaction conditions (Scheme [12]).[28a] The hexaarylated aza-BODIPYs 45a–f exhibited absorption (λ_max = 653–656 nm) and fluorescence bands (λ_em = 688–750 nm) hypsochromically shifted by 7–10 nm compared with the meso-tetraaryl aza-BODIPYs 2 (λ_max = 663 nm). The hexaarylated aza-BODIPYs 45a–f were also found to be weakly fluorescent with low quantum yields (Φ_f = 0.01–0.05) and short singlet-state lifetimes (τ = 0.06-0.26 ns) compared with 1,3,5,7-tetraaryl aza-BODIPYs 2 (Φ_f = 0.25; τ = 1.56 ns). Later in 2021, Hayvalı and co-workers introduced 4-(diphenylamino)phenyl and 4-(methoxy)phenyl groups at the 2- and 6-positions of aza-BODIPYs by using 38c with a catalytic amount of Pd(PPh₃)₄ and K₂CO₃ at 85 °C for 24 hours under similar Suzuki–Miyaura cross-coupling conditions to afford compounds 45g and 45h, respectively (Scheme [12]).[32]

The diiodo(tetraaryldipyrromethene)s 46a–c were used to prepare several n-type p-phenylene ethynylene-conjugated polymers. The reactions of 46a–c with 1,4-bis[(2-ethylhexyl)oxy]-2,5-diethynylbenzene in dry chlorobenzene/TEA in the presence of catalytic amount of Pd(PPh₃)₄/CuI at 40 °C for two days under Sonogashira conditions afforded the azadipyrromethene-based polymers 47a–c in yields of 36–76% (Scheme [13]).[33] The azadipyrromethene based polymers 47a–c were treated with boron triflate in chlorobenzene in presence of N,N-diisopropylethylamine at 50 °C for 24 hours to afford the aza-BODIPY-based polymers 48a–c in yields of 83–96%. The authors’ studies also indicated that the aza-BODIPY based polymers 48a–c cannot be synthesized directly from the BF₂-chelated aza-BODIPY monomers. The aza-BODIPY-based polymers 48a–c absorb strongly in the red–NIR region, with an absorption band tailing up to 1000 nm. The studies also indicated that BF₂ complexation of the azadipyrromethene based polymers 47a–c helps in enhancing the planarity of the polymer backbone for effective π–π stacking.

The Andraud group also followed a similar post-coupling strategy to synthesize the aza-BODIPY dyes. Products 50a and 50b, containing chromophores at the 2- and-6 positions, were prepared by starting from 46d and proceeding via 49a or 49b through a Sonogashira coupling in the presence of a catalytic amount of Pd(PPh₃)₄ in THF at 20 °C for one hour, followed by complexation with BF₃·OEt₂ in DIPEA at 110 °C for five to six hour (Scheme [13]); the products exhibit broad absorption bands.[34]

Zhu and co-workers synthesized three novel donor-π-acceptor (D-π-A) aza-BODIPY-conjugated polymers by treating the 2,6-diiodo aza-BODIPY 39a with 3,6-diethynyl-9-octyl-9H-carbazole, 3,7-diethynyl-10-octyl-10H-phenathiazine, or 3,6-diethynyl-10-octyl-10H-phenathiazine S,S-dioxide under Pd-catalyzed Sonogashira coupling conditions with Pd(PPh₃)₂ and CuI in THF/Et₃N at 40 °C for two days: the corresponding D-π-A aza-BODIPY-conjugated polymers 51a–c were obtained in yields of 65-73% [Scheme [14](i)].[35] The D-π-A aza-BODIPY-conjugated polymers 51a–c showed one shorter-wavelength band at 450 nm and one intramolecular charge-transfer band in the longer-wavelength region 710–729 nm. The presence of different electron-donating units strongly influenced the absorption spectra, leading to visible color changes for the three polymer solutions. The lower band gaps in the three polymers 51a–c compared with those of the monomers indicated a potential light-harvesting behavior. The three polymers showed weak emissions with emission band maxima in the range 740–765 nm, as well as low quantum yields, which were attributed to the rapid intramolecular charge transfer from the electron-rich donor to the electron-deficient acceptor units. Cheng and co-workers synthesized the nonclassical polycatenary 52 by treating diiodo aza-BODIPY 39b with an α-cyanostilbene borate through Suzuki coupling in the presence of Pd(PPh₃)₂ in THF–H₂O at 78 °C for 15 hours [Scheme [14](ii)]. The product shows a twisted intramolecular charge-transfer effect in the solution state, and can be used as a fluorescent imaging agent.[36]

Misra and co-workers[37] used the 2,6-diiodo aza-BODIPY 39c to synthesize the ferrocenyl aza-BODIPY 53 by treating it with ethynylferrocene under Pd-catalyzed Sonogashira cross-coupling reaction conditions in the presence of Pd(dba)₂ (dba = dibenzylideneacetone) and AsPh₃ in degassed DMF–TEA at 80 °C for 48 hours (Scheme [15]). However, during reaction, the BF₂ fragment was lost, and authors isolated the disubstituted ferrocenyl azadipyrromethene, which was then treated with BF₃·OEt₂ in the presence of N,N-diisopropylethylamine in CH₂Cl₂ overnight at room temperature to afford the 2,6-diferrocenyl aza-BODIPY 53 in 25% yield (Scheme [15]). The 2,6-diferrocenyl aza-BODIPY 53 showed one strong absorption band at 653 nm and a shoulder band at 800 nm, which was an intramolecular charge-transfer band. The 2,6-diferrocenyl aza-BODIPY 53 was nonemissive, due to the rapid nonradiative deactivation of its excited state with intramolecular charge transfer.

Ravikanth and co-workers subjected the nonsymmetrically 2,6-difunctionalized aza-BODIPY 41, containing a formyl and a bromo group, to Wittig reactions with three different phosphonium ylides under simple reaction conditions at room temperature for one to two hours to afford the conjugated aza-BODIPYs 54a–c in high yields (Scheme [16]).[20] The Wittig conjugates 54a–c, containing a bromo functional group on the β-pyrrole group, were then treated with anisylboronic acid in a 1:1:1 toluene–THF–H₂O mixture in the presence of Pd(PPh₃)₄ and Na₂CO₃ at 70 °C for one to two hours, followed by column chromatographic purification, to afford the 1,2,3,5,7-pentaaryl aza-BODIPY conjugates 55a–c in good yields. The method worked efficiently and provides a useful strategy for introducing various substituents on the aza-BODIPY core. Absorption and fluorescence spectral studies of 55a–c indicated that the absorption (λ_max = 662–667 nm) and emission bands (λ_em = 702 nm) were red-shifted and broadened compared with those of 1,3,5,7-tetraaryl aza-BODIPYs 2 (λ_max = 665 nm; λ_em = 695 nm), indicating that substituents on the 2- and 6-positions of aza-BODIPYs alter the electronic properties of the compounds.

3,5-Difunctionalized Aza-BODIPYs

As shown in Scheme [1], the synthesis of symmetrical 1,3,5,7-tetraaryl aza-BODIPYs 2 requires a sequence of four steps.[38] However, the resulting functionalized aza-BODIPYs are useful for preparing aza-BODIPY-based fluorescent compounds; consequently, researchers have explored various approaches for synthesizing aryl-functionalized aza-BODIPYs. The 3,5-difunctionalized 1,3,5,7-tetraaryl aza-BODIPYs 61a–e, containing various functionalized aryl groups, such as p-bromophenyl or p-hydroxyphenyl, were prepared as shown in Scheme [17]. Aldol condensation of arylacetophenones 56a–c with aryl aldehydes 57a–c in MeOH in the presence of NaOH at room temperature for 15–25 hours gave the corresponding chalcones 58a–e. These underwent Michael addition with nitromethane and diethylamine at the reflux for 12 hours to give the nitrochalcones 59a–e. Nitrochalcones 59a–e were treated with ammonium acetate at the reflux for 24 hours under an inert atmosphere, followed by column chromatographic purification, to afford the difunctionalized azadipyrromethenes 60a–e. Reaction of 60a–e with BF₃·OEt₂/DIPEA in CH₂Cl₂ afforded the corresponding 3,5-difunctionalized tetraaryl aza-BODIPYs 61a–e in good yields.

The 3,5-bis(4-bromophenyl)-1,7-bis[4-(dimethylamino)phenyl] aza-BODIPY 61a was used to prepare several interesting aza-BODIPY-based conjugates 62a–c, as shown in Scheme [18]. Treatment of 61a with (4-ethynylphenyl)(dimesityl)borane in THF–triethylamine containing Pd(PPh₃)₄ and CuI under Sonogashira reaction conditions at the reflux overnight afforded the 3,5-bis{[(4-diarylboranatophenyl)ethynyl]phenyl}-substituted aza-BODIPY 62a in 57% yield.[39] Aza-BODIPY 62a showed one broad absorption band at 336 nm, accompanied by a shoulder band at 385 nm, and another broad band at around 660 nm, with a fluorescence quantum yield of 3.2%. Photophysical studies of 62a revealed a partial energy transfer from the blue triarylborane fluorophore to the aza-BODIPY NIR chromophore, leading to a broad emissive feature covering a large part of the visible and NIR region. By carrying out fluorescence titration experiments, the authors also showed that compound 62a can act as a selective fluoride-anion sensor.

The aza-BODIPY 61a was also used to synthesize the aza-BODIPY-based compounds Aza-Bthp (62b) and Aza-Sty (62c) through reaction with the appropriate boronic acids in the presence of Cs₂CO₃ base and Pd(dppf)Cl₂ [dppf = 1,1′-bis(diphenylphosphino)ferrocene] catalyst in refluxing 1:1:0.15 THF–toluene–H₂O at 100 °C for six hours under Suzuki coupling conditions (Scheme [18]).[40]

The aza-BODIPY based compound, Aza-Fhdt (63) was synthesized in two steps. In the first step, Aza-FCHO (62d), was synthesized by coupling compound 61a with (4-formyl-2-furyl)boronic acid under Suzuki coupling conditions to afford Aza-FCHO (62d), which on Horner–Wittig reaction with 4,5-bis(hexylsulfanyl)-1,3-dithiole-2-thione in the presence of triethyl phosphite in refluxing dry toluene for 40 minutes afforded Aza-Fhdt (63; Scheme [18]). The aza-BODIPY donor molecules 62b–d and 63 exhibit a panchromatic absorption spanning approximately 280–1000 nm. These compounds have been tested as donors in organic solar-cell applications. The studies revealed that under the optimized conditions, using PC70BM as an acceptor, power-conversion efficiencies (PCE%) of 2.44, 2.52, and 1.20 were achieved for Aza-Bthp (62b), Aza-Sty (62c), and Aza-Fhdt (63), respectively.

Other 3,5-disubstituted aza-BODIPYs with an extended π-conjugated skeleton were synthesized from the difunctionalized azadipyrromethene 60a [Scheme [19](i)].[41] Azadipyrromethene 60a was treated with (9,9-dipropyl-9H-fluoren-2-yl)boronic acid in the presence of a catalytic amount of Pd(PPh₃)₄ in K₂CO₃ at 85 °C for 24 hours under Suzuki reaction coupling conditions to yield compound 64, which was then treated with BF₃·OEt₂ in CH₂Cl₂ at room temperature for two days in the presence of N,N-diisopropylethylamine to afford the aza-BODIPY 65 ,which showed an external quantum efficiency of 18.15% at 840 nm, and can be used as a NIR organic photodetector.

The dibromo azadipyrromethene 60b reacted with various ethynylarenes under copper-free Sonogashira cross-coupling conditions, with Pd(PPh₃)₄ as a catalyst, to afford the azadipyrromethenes 66a–d containing π-conjugated extended chromophores [Scheme [19](ii)].[34] [42] The donor-substituted azadipyrromethenes 66a–d were treated with BF₃·OEt₂ and Hünig’s base to afford the 3,5-π-conjugated dichromophore-substituted aza-BODIPYs 67a–d in yields of 50–90%. The absorption and emission spectra of compounds 67a–d were significantly red-shifted (λ_abs = 660–716 nm; λ_em = 700–741 nm) compared with 1,3,5,7-tetraphenyl aza-BODIPY 2a (λ_abs = 650 nm; λ_em = 672 nm), and the compounds showed good quantum yields in the range 0.25–0.36.

D’Souza, Fukuzumi, and co-workers used aza-BODIPY 61c, containing 4-hydroxyphenyl groups at the 3- and 5-positions, to synthesize the donor–acceptor dyad 68 and triad 69, which can act as electron-transfer and light-harvesting complexes (Scheme [20]).[43] The 3,5-bis(4-hydroxyphenyl) aza-BODIPY 61c was treated with 4-ferrocenylbenzoic acid in the presence of EDCI at 0 °C for 24 hours in DMF, followed by chromatographic purification, to afford monoferrocenyl-substituted aza-BODIPY 68 and diferrocenyl aza-BODIPY 69 in decent yields. Steady-state fluorescence and transient-absorption studies indicated the possibility of an efficient electron transfer from the ferrocene unit(s) to the aza-BODIPY unit, resulting in significant quenching of the fluorescence of the aza-BODIPY unit in the dyad 68 and triad 69.

The same research group also synthesized the covalently linked BODIPY–aza-BODIPY dyad 71 and the (BODIPY)₂–aza-BODIPY triad 73 by using the 3,5-bis(4-hydroxyphenyl) aza-BODIPY 61c as a building block (Scheme [21]).[44] Compound 61c reacted with 4-formylbenzoic acid in the presence of EDCI at 0 °C for 24 hours to afford aza-BODIPYs containing one (70) or two 4-formylphenyl groups (72). In the next step, the formylphenyl-containing aza-BODIPYs 70 and 72 reacted with 2,4-dimethylpyrrole in absolute dichloromethane and TFA for three hours at room temperature to give the corresponding aza-BODIPYs containing one or two dipyrromethene entities; these were then treated with DDQ for one hour, followed by addition of BF₃·OEt₂/DIPEA at room temperature for one hour, to afford the BODIPY–aza-BODIPY dyad 71 and the (BODIPY)₂–aza-BODIPY triad 73, respectively, in good yields. The authors carried out detailed steady-state and time-resolved studies to show an efficient energy transfer (~10¹¹ s^–1) from the BODIPY to the aza-BODIPY in the dyad 71 and the triad 73.

D’Souza, Fukuzumi, and co-workers also used the the bis(4-hydroxyphenyl) aza-BODIPY 61c to synthesize the covalently linked aza-BODIPY–Zn(II)porphyrin dyad 74 and the aza-BODIPY–[Zn(II)porphyrin]₂ triad 75 (Scheme [22]), which they used as supramolecular clips to host a three-dimensional electron-acceptor fullerene through a two-point metal–ligand axial coordination.[45] The 3,5-bis(4-hydroxyphenyl) aza-BODIPY 61c was treated with 5-(4-carboxyphenyl)-10,15,20-triphenylporphyrin (H₂TPP) in the presence of EDCI in DMF at 0 °C for 24 hours, followed by column chromatographic purification, to afford an aza-BODIPY–H₂TPP dyad and an aza-BODIPY-(H₂TPP)₂ triad, which were then treated with Zn(OAc)₂ in CHCl₃–MeOH at room temperature for 12 hours, followed by purification by column chromatography, to afford the aza-BODIPY–Zn(II)TPP dyad 74 and the aza-BODIPY–(Zn(II)TPP)₂ triad 75. Photophysical studies revealed an efficient singlet–singlet energy transfer from ZnTPP* to aza-BODIPY in both the dyad 74 and the triad 75 in toluene or o-dichlorobenzene, whereas in more-polar solvents, an additional electron transfer was also observed, along with energy transfer. The authors also generated a supramolecular tetrad by assembling a bispyridine-functionalized fullerene with the aza-BODIPY–(Zn(II)TPP)₂ triad 74 through a two-point metal–ligand axial coordination and, by using femtosecond transient-absorption spectral studies, they demonstrated that electron transfer occurs from the photoexcited Zn(II) porphyrin to the fullerene. Furthermore, a photochemical cell fabricated with a FTO/SnO₂/tetrad electrode showed an incident photon-to-current conversion efficiency of up to 17%.

Zhu, Guo, and co-workers developed the aza-BODIPY-based NIR-emitting ratiometric fluorescent probes 76–78 (Scheme [23]).[46]. One hydroxy group in aza-BODIPY 61c was replaced by treating it with propargyl bromide and cesium fluoride in DMF at room temperature for 16 hours to afford the alkynylated aza-BODIPY 61f. Compound 61f then reacted with [4-(hydroxymethyl)phenyl]boronic acid pinacol ester in the presence of triphosgene and CH₂Cl₂/DIPEA at room temperature for one hour to give the aza-BODIPY probe 76. Aza-BODIPY 76 was further functionalized with a hydrophilic biotin–PEG₅ segment to enhance its solubility, yielding compound 77. This fluorescent probe 77 was used to track endogenous H₂O₂ in living cells and tumor-bearing mice. The aza-BODIPY probe 78 was synthesized by treating compound 61f with [4-(2-bromoethyl)phenyl]boronic acid pinacol ester in DIPEA–MeCN at 80 °C for eight hours under similar reaction conditions.

The aza-BODIPY 61c was used by Tasior and O’Shea in a synthesis of the aza-BODIPY-based NIR fluorochromes 79–82, as shown in Scheme [24].[47] Compound 61c reacted with various alcohols, polyether triethylene glycol monomethyl ether, and N-Boc-protected ethanolamine in THF–PPh₃ at room temperature for 24 hours, followed by column chromatography, to yield aza-BODIPY 79. The N-Boc group of aza-BODIPY 79 was deprotected in the next step by using TFA in CH₂Cl₂ at room temperature for two hours to afford compound 80. The carboxylate group in compound 80 was converted into a corresponding ester by treatment with N-hydroxysuccinimide or N-hydroxysulfosuccinimide sodium salt in CH₂Cl₂ containing EDCI and DMAP at room temperature for 16 hours to give aza-BODIPYs 81a and 81b. Finally, the fluorophore aza-BODIPY 82 was obtained from 81a or 81b by coupling with N-Boc-l-Lysine in organic and aqueous media, respectively, at room temperature for 15–60 min. Studies showed that the fluorophore 82 formed conjugates with amino acids and proteins, and showed emission maxima above 720 nm.

O’Shea and co-workers also prepared the water-soluble aza-BODIPYs 83 and 86 by incorporating sulfonic and carboxylic acid motifs, using 3,5-bis(4-hydroxyphenyl) aza-BODIPY 61c or the azadipyrromethene 60c as precursors (Scheme [25]).[48] The disulfonic acid-functionalized derivative 83 was prepared in 41% yield by treating 3,5-bis(4-hydroxyphenyl) aza-BODIPY 61c with propane-1,3-sultone in the presence of K₂CO₃ in refluxing acetone for six hours. Treatment of the bis(4-hydroxyphenyl)azadipyrromethene 60c with methyl bromoacetate in the presence of K₂CO₃ in refluxing acetone for 16 hours, followed by column chromatographic purification, afforded the diester derivative 84, which was then saponified with potassium trimethylsilanolate (TMSOK) in THF at room temperature for three hours, followed by BF₂ complexation, to afford the water-soluble dicarboxylic acid derivative 86. Both the water-soluble aza-BODIPYs 83 and 86 were strongly fluorescent in the NIR emission region (>720 nm) with decent quantum yields of 0.30–0.31. The authors carried out fluorescence-imaging studies and found that fluorophores 83 and 86 could be readily imaged in both eukaryotic and prokaryotic cells.

Sengupta and co-workers synthesized the polychromophoric aza-BODIPY triads 88a and 88b by treating aza-BODIPY 61d with azides 87a and 88b, respectively, in the presence of sodium ascorbate under standard copper-catalyzed conditions in a 12:1:1 mixture of dichloromethane, EtOH, and water at room temperature for 24 hours (Scheme [26]).[49] Triads 88a and 88b exhibited efficient energy transfer (99.3–99.7%) from the perylenediimide units to the aza-BODIPY units.

ortho-Difunctionalized azadipyrromethenes containing such functional groups as 2-bromophenyl (91a and 91b) or 2-hydroxyphenyl (91c and 91d) in the 3- and 5-positions were also synthesized by standard synthetic routes, as shown in Scheme [27].[50] [51] The first step involved the nitration of the appropriate functionalized chalcones 89a–d with nitromethane in refluxing diethylamine overnight under Henry reaction conditions to afford the functionalized nitrochalcones 90a–d. These were then treated with ammonium acetate in refluxing ethanol for 24 hours to give the azadipyrromethenes 91a–d.

The bis(2-bromophenyl) azadipyrromethenes 91a and 91b reacted with two equivalents of bromine in CH₂Cl₂ at room temperature for five minutes to afford the tetrabrominated azadipyrromethene 92a and 92b, respectively. These reacted with S₈ in the presence of a catalytic amount of CuI and Na₂CO₃ at 130 °C for 15 hours to afford the dibenzothiophene[β]-fused azadipyrromethenes 93a and 93b, which were then complexed with BF₃·OEt₂ in the presence of Et₃N at 65 °C for two hours to afford the bis-benzothiophene-fused aza-BODIPYs 94a and 94b in yields of 77–80% (Scheme [28]).[50] X-ray structural analysis of aza-BODIPY 94a revealed that the parent skeleton was slightly distorted (Figure [5]). The absorption and fluorescence spectra of bis-benzothiophene-fused aza-BODIPYs 94a and 94b showed significant red shifts. They absorb strongly in the 600–800 nm region, but emit weakly.

Treatment of the bis(phenolate) azadipyrromethenes 91c and 91d with BF₃·OEt₂ in the presence of DIPEA in THF at reflux for 12 hours, followed by column chromatographic purification, afforded the aza-BODIPYs 95a and 95b in yields of 45–52% (Scheme [29]).[51] An X-ray structural analysis of aza-BODIPY 95a revealed that both phenolic rings showed significant flexibility to coordinate with the B(III) ion with a tetrahedral geometry. The B(III) complexes 95a and 95b showed a strong absorption and emission in the NIR region with quantum yields of up to ~14%.

1,7-Disubstituted Aza-BODIPYs

A series of 1,7-di-p-functionalized-aryl aza-BODIPYs 101a–g were synthesized by following the classical route for the synthesis of aza-BODIPYs (Scheme [30]).[12a] [b] [52] Functional groups such as –Br, –OH, –CN, –CH₂OH, and –N-(CH₂–C≡H)₂, have been introduced on the aryl groups present at the 1- and 7-positions of aza-BODIPYs, as shown in Scheme [30]. The 1,7-difunctionalized aza-BODIPYs 96a–g were prepared in four steps by the aldol condensation of para-functionalized aryl aldehydes 96 and substituted acetophenones 97 at room temperature for 24 hours to afford chalcones 98a–f. Michael addition of chalcones 98a–f with nitromethane at the reflux for 24 hours afforded nitrochalcones 99a–f. These were condensed with ammonium acetate to obtain the azadipyrrins 100a–f, and subsequent BF₂ complexation at room temperature for 30–60 minutes afforded the aza-BODIPYs 101a–f . The aza-BODIPY 101e was oxidized with MnO₂ in CH₂Cl₂ at room temperature for 30 hours to afford the 1,7-di(p-formylphenyl) aza-BODIPY 101g. The 1,7-difunctionalized aza-BODIPYs have been used to prepare several interesting compounds.

O’Shea and co-workers reacted the 1,7-bis(hydroxyphenyl) aza-BODIPY 101a with 1,2-oxathiane 2,2-dioxide in dry THF and Cs₂CO₃ under reflux for 16 hours to afford the bis(alkylsulfonic acid)-substituted aza-BODIPY 102 [Scheme [31](i)].[53] In DMSO, the bis(alkyl sulfonic acid)-substituted aza-BODIPY 102 absorbs and emits at 786 and 826 nm, respectively, with a low quantum yield of 0.01. Compound 102 has potential utility for fluorescence imaging in biological applications.

Gul and co-workers prepared aza-BODIPY 103 with phthalonitrile substituents by treatment of aza-BODIPY 101b with 4-[(3,4-dicyanophenyl)sulfanyl]benzoic acid in the presence of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-(N,N-dimethylamino)pyridine (DMAP) in dry tetrahydrofuran under inert conditions at room temperature for 48 hours [Scheme [31](ii)].[54] Studies indicated that aza-BODIPY 103 can be used as a drug in various biological applications, as its effectiveness has been examined on the MCF-7 breast cancer cell line and the L929 cell line, a line of normally healthy cells.

The 1,7-di(4-bromophenyl) azadipyrromethene 100c was subjected to Sonogashira cross-coupling with 4-ethynyl-N,N-dihexylaniline in the presence of a catalytic amount of Pd(PPh₃)₄ and K₂CO₃ in DMF at 110 °C for 20 hours, followed by chromatographic purification, to afford the corresponding azadipyrromethene 104 in 18% yield (Scheme [32]).[34] BF₂ complexation of substituted azadipyrromethene 104 with DIPEA in CH₂Cl₂ at 20 °C for 12 hours, followed by simple column chromatographic purification, afforded the 1,7-disubstituted aza-BODIPY 105.

The aza-BODIPY 101d containing diethynylamino functional groups at the 1- and 7-positions was subjected to a click reaction with an azide in the presence of CuSO₄/sodium ascorbate in DCE–EtOH–H₂O at room temperature overnight to afford the aza-BODIPY dye 106 in 23% yield (Scheme [33]).[55] Dye 106 absorbs at 748 nm and emits at 843 nm, and studies showed that it can be used as an NIR probe for the Hg²⁺ ion.

Similarly, the di-meta-functionalized 1,7-diaryl aza-BODIPYs 108a and 108b containing –NO₂, and -CH₂OH functional groups, respectively, were also synthesized by the four standard steps (Scheme [34]). The di-meta-functionalized azadipyrromethenes 107a and 107b were complexed with BF₃·OEt₂ in CH₂Cl₂ in the presence of Hünig’s base at room temperature at 24 hours to afford the corresponding di-meta-functionalized 1,7-diaryl aza-BODIPYs 108a and 108b, respectively.[56] The aza-BODIPY 108a was oxidized with MnO₂ in CH₂Cl₂ at room temperature for 30 hours to afford the 1,7-di(m-formylphenyl) aza-BODIPY 108c.

The meta- and para-diformyl aza-BODIPYs 101g and 108c, respectively, reacted with excess pyrrole in the presence of a catalytic amount of BF₃·OEt₂ at room temperature for 15 minutes, followed by column chromatographic purification, to afford 1,7-dipyrromethanyl aza-BODIPYs 109 and 110, respectively, in yields of 20–70% yield (Scheme [35])[56]. Oxidation of compounds 109 and 110, followed by BF₂ complexation at room temperature for 30 minutes, afforded the 1,7-(BODIPY)₂–aza-BODIPY triads 111 and 112, respectively, in yields of 25–26%. Triad 111 exhibited absorption bands at 480 675, and 506 nm, and similar bands were observed for triad 112.

The 1,7-bis(m-nitrophenyl) azadipyrromethene 107b was reduced by treating it with Pd/C in CH₂Cl₂–MeOH at room temperature for 24 hours, followed by treatment with BF₃·OEt₂/DIPEA in CH₂Cl₂ at room temperature for 24 hours, to afford 1,7-bis(m-aminophenyl) aza-BODIPY 113 in 49% yield (Scheme [36]).[57] The 1,7-bis(m-aminophenyl) aza-BODIPY 113 was subjected to nucleophilic addition with phenyl isothiocyanate in MeCN–CH₂Cl₂ (9:1) at room temperature for 24 hours, followed by chromatographic purification, to afford the 1,7-bis(diphenylthiourea)-substituted aza-BODIPY 114 in 33% yield. The dye 114 absorbs and emits strongly in the NIR region (λ_abs = 690 nm; λ_em = 725 nm), and selectively detects Cu²⁺ ion in aqueous buffer solution and in HepG2 cells.[57]

The 1,7-bis(m-aminophenyl) aza-BODIPY 113 was further derivatized by treating it with bromoacetyl bromide in CH₂Cl₂–Et₃N at room temperature for 18 hours to afford the 1,7-bis[m-(bromoacetamido)phenyl] aza-BODIPY 115 (Scheme [36]).[58] This was further treated with 1-[6-(aminomethyl)pyridin-2-yl]-N,N-bis(pyridin-2-ylmethyl)methanamine in DMF–DIPEA at 40 °C for 24 hours, followed by alumina column chromatography, to afford the 1,7-substituted aza-BODIPY fluorophore 116 in 67% yield. Fluorophore 116 was used as an exclusive probe for Cd²⁺ ion in environmental samples and living cells, as judged from absorption and fluorescence studies.

Miscellaneous

Some miscellaneous examples of functionalized aza-BODIPYs reported in the literature cannot be placed in any of the previous sections. The 3,5-functionalized aza-BODIPYs 117a and 117b were treated with different amounts of NIS in CHCl₃–AcOH at the reflux for five to ten hours to afford the tetrahalogenated aza-BODIPYs 118a and 118b and the hexahalogenated aza-BODIPYs 119a and 119b (Scheme [37]).[28c] [29] Aza-BODIPYs 117a and 117b exhibited absorption bands in the red region (660–675 nm), which were blue-shifted compared with the absorption spectra of the core substituted aza-BODIPYs 118a and 118b respectively, whereas the aza-BODIPY derivatives 119a and 119b, which had substitutions both at their peripheries and in their cores, exhibited absorption maxima at 666 and 676 nm, respectively. Studies revealed that the hexahalogenated aza-BODIPYs 119a and 119b exhibited high triplet quantum yields (Φ_T = 0.78–0.86) and high singlet-oxygen generation efficiencies, and can be used as photooxygenation catalysts.

Burgess and co-workers prepared the 1,3,5,7-tetrafunctionalized aza-BODIPYs 122 and 123 by the sequence of steps shown in Scheme [38], and used the products in energy-transfer dye cassette systems.[59] The 3,5-difunctionalized aza-BODIPY 61e was treated with BBr₃ in dry CH₂Cl₂ at room temperature for two hours to deprotect the methoxy groups and afford the unstable 1,3,5,7-tetrafunctionalized aza-BODIPY 120; this was then reacted with methyl bromoacetate in dry THF at room temperature for 12 hours to afford the stable aza-BODIPY 121. This was coupled with 5-ethynyl-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-3′,6′-diyl diacetate in the presence of a catalytic amount of PdCl₂(PPh₃)₂ and CuI in THF at 35 °C for two hours to afford the 3,5-difluorescein-functionalized aza-BODIPY 122 (Scheme [38]).[59] This was hydrolyzed with solid TMSOK in THF at room temperature for two hours to afford the fluorescein–aza-BODIPY cassette 123. Studies revealed that the energy-transfer efficiency between the aza-BODIPY and the fluorescein units in the energy-transfer cassettes 122 and 123 is poor.

The 3,5-(meta-dimethylamino)phenyl-functionalized aza-BODIPY 124 was treated with NBS in CH₂Cl₂ at room temperature for 5–30 minutes to afford the dibromo- and tetrabromo-functionalized aza-BODIPYs 125 and 126, respectively (Scheme [39]).[60] These dyes showed efficient singlet-oxygen generation in the range 0.36–0.58.

Yin and co-workers treated the 3,5-(3,4-dimethoxyphenyl)-substituted aza-BODIPY 127 with BBr₃ in CH₂Cl₂ at room temperature for two hours to afford the 3,5-dicatechol-functionalized aza-BODIPY 128 (Scheme [40]).[61] The dye 128 was mixed with Fe³⁺ to prepare Fe-containing nanoparticles that were used for therapeutic nanomedicine applications. The absorption peak of aza-BODIPY 128 at 717 nm gradually decreased upon dropwise addition of FeCl₃, and a new peak appeared at 960 nm, extending into the NIR-II region.

The functionalized aza-BODIPY 129 was used to prepare the covalently linked (BODIPY)₂–aza-BODIPY triads 130 and 131 (Scheme [41]).[62] The aza-BODIPY 129 reacted with the azide functionalized BODIPYs 132a and 132b in the presence of sodium ascorbate and copper(II) sulfate at room temperature for 20–24 hours under click reaction conditions to afford the triazole-bridged (BODIPY)₂–diiodo aza-BODIPY triad 130 and the (carbazole–styryl-BODIPY)₂–diiodo aza-BODIPY 131 (Scheme [41]).

The authors’ studies confirmed the existence of efficient intramolecular energy transfer from the BODIPY moiety to the aza-BODIPY moiety in these triad systems. Their studies also indicated that the multichromophore systems 130 and 131 can be effectively used as triplet photosensitizers for singlet-oxygen generation, with quantum yields of 0.15–0.53.

There are few approaches available for the synthesis of functionalized alkyl-substituted aza-BODIPYs.[63] The 1,7-dimethyl -3,5-di(anisyl) aza-BODIPY 136 was prepared as shown in Scheme [42]. Reaction of but-2-en-1-al with phenyllithium and (p-methoxyphenyl)magnesium bromide in THF at 0 °C for one hour afforded the enol 133, which was oxidized with MnO₂ at room temperature for 20 hours to give the α,β-unsaturated ketone 134. This was then nitrated under Michael addition conditions with MeNO₂ at the reflux for five hours to afford the nitrochalcone 135. In a subsequent step, nitrochalcone 135 reacted with NH₄OAc in EtOH at the reflux for ten hours to afford the corresponding azadipyrrin 136

Azadipyrrin 136 was then treated with BBr₃ in CH₂Cl₂ at –78 °C for three hours to yield the functionalized aza-DIPY 137, which was complexed with BF₃·OEt₂ in CH₂Cl₂ at room temperature for 20 hours to afford the functionalized aza-BODIPY 138 (Scheme [43]).[52d] Functionalized aza-BODIPY 138 was treated with 1,3-propanesultone and cesium carbonate in THF at the reflux for one hour to give the aza-BODIPY 139, which was soluble in both organic solvents and water. In phosphate-buffered saline (PBS), aza-BODIPY 139 showed a broadening in the absorption spectrum at 651 nm and an emission maximum at 691 nm.

In recent times, fused and conformationally restricted aza-BODIPYs have been synthesized by adopting various strategies.[64] Xiao and co-workers synthesized the symmetrical pyrene-containing aza-BODIPY 142 by using 9,10,12a,12b-tetrahydrobenzo[def]chrysen-7(8H)-one (140) as starting precursor. Compound 140 was treated with 3-phenyl-2H-azirene in the presence of NaH at –40 °C for one hour to afford compound 141, which was then condensed with NaNO₂ in the presence of AcOH/Ac₂O, followed by complexation with BF₃·OEt₂/Et₃N at 80 °C for 30 minutes, to afford the pyrene-fused aza-BODIPY 142(Scheme [44]).[65] Aza-BODIPY 142 is very rigid and absorbs and emits in the NIR region (λ_max = 746 nm; λ_em = 762 nm ) as a combined result of the rigidization and the extension of the π-conjugation.

Similarly, Zhao, Chan, and co-workers synthesized conformationally restricted aza-BODIPY 145 by first condensing the pyrrole monomer 143 with NaNO₂ in the presence of acetic acid followed by subsequent addition of N,N-diethyl-4-(4-phenyl-1H-pyrrol-2-yl)aniline at 80 °C for 30 min. to afford azadipyrromethene 144, which was further complexed with BF₃·OEt₂/Et₃N at 80 °C for 30 minutes (Scheme [45]).[66] This aza-BODIPY 145 acts as probe for the detection of tumor hypoxia, as established from in vivo studies.

Recently, the Borisov group synthesized aza-BODIPYs 148, 151, and 155 in three steps each, by adopting a similar method. The symmetrical azadipyrromethenes 147 and 150 were synthesized by condensing the respective pyrrole precursors 146 and 149 with NaNO₂ in the presence of propionic acid at –10 °C. The symmetric azadipyrromethenes 147 and 150 were then complexed with BF₃·OEt₂ at room temperature for 15 minutes to afford the symmetrical aza-BODIPYs 148 and 151 [Schemes 46(i) and (ii)].[67] Unsymmetrical aza-BODIPY 155 was synthesized by nitrosation of compound 152 with sodium nitrite in propionic acid at –10 °C, followed by the addition of the carbazole-substituted pyrrole 149 in acetic anhydride to afford the nonsymmetrical azadipyrromethene intermediate 153 [Scheme [46](iii)]. BF₂ chelation of 153 at room temperature for 15 minutes gave aza-BODIPY 154, which was further deprotected with KOAc in DMF at room temperature for one hour to yield aza-BODIPY 155. The aza-BODIPY dyes 148, 151, and 155 absorb and emit in the NIR region (λ_max = 734–791 nm; λ_em = 741–800 nm), with quantum yields of 0.16 to 0.49.

Conclusions

BF₂ complexes of dipyrrins (BODIPYs) are versatile dyes that can be readily synthesized and whose photophysical properties can be easily tuned by the introduction of suitable substituents onto the pyrrole moieties to provide products that have been used in a wide range of applications from materials to medicine. Aza-BODIPYs, which are the result of replacing the meso-carbon with a nitrogen atom, possess altered photophysical properties compared with BODIPYs. Aza-BODIPY dyes are more stable and absorb more strongly in the far-red region, with good quantum yields. However, their synthesis involves four steps and difficult chromatographic purifications, unlike BODIPYs which can be synthesized readily in two steps. The chemistry of BODIPYs has grown tremendously because these dyes can be readily functionalized, and the functionalized BODIPYs can be used as building blocks to synthesize a variety of BODIPY-based fluorophores. On the other hand, there are limited reports available on functionalized aza-BODIPYs, because the 1-, 3-, 5-. and 7-positions are generally occupied by aryl groups, because these 1,3,5,7-tetraaryl aza-BODIPYs are more stable and the methods used for their synthesis are well-established in the literature. However, various methods have been exploited in recent times to introduce functionalized aryl groups at the β-pyrrole positions and to synthesize aza-BODIPY-based water-soluble compounds and energy-transfer cassettes. The water-soluble aza-BODIPYs have been used for biological imaging and photodynamic therapy applications. Functional groups have also been introduced directly at the 2- and 6-positions, and sterically crowded aza-BODIPYs and aza-BODIPY–BODIPY dyads and triads have been prepared. Although some functionalized aza-BODIPYs have been synthesized, there is a wide scope for developing methods to synthesize functionalized aza-BODIPYs that can be used as building blocks for the synthesis of interesting aza-BODIPY-based compounds for various applications. We hope to see such developments in the chemistry of aza-BODIPY dyes in the near future.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank IITB, Government of India, for infrastructural facilities, and our co-workers whose names are mentioned in the references.

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Corresponding Author

Publication History

Received: 20 March 2023

Accepted after revision: 19 June 2023

Article published online:
17 August 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
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