Synthesis and Studies of BODIPY‐Ferrocene Conjugates: An Overview

ABSTRACT

Boron(III) difluoro dipyrromethene (BODIPY) dyes are known for their strong absorption, high fluorescence quantum yields, narrow emission bands, and high photostability. These properties make them suitable for sensing, imaging, and therapeutic applications. The incorporation of the redox‐active ferrocene unit into the BODIPY framework yields donor–acceptor hybrid systems with fascinating electronic and photophysical properties. In these systems, photoinduced electron transfer often triggers fluorescence quenching and facilitates reversible electrochemical control of excited states. Structural modification of the BODIPY core, particularly through the incorporation of π‐conjugated linkers (e.g., C═C and C≡C bonds) at the meso‐ and pyrrolic positions, extends the conjugation. These modifications enhance electronic communication between donor ferrocene and acceptor BODIPY and allow the incorporation of auxiliary units like porphyrin, pyrene, fullerene, and biotin. This review highlights recent advances in the synthesis of BODIPY‐ferrocene conjugates using Sonogashira coupling, Knoevenagel condensation, and click chemistry. Their spectroscopic, electrochemical, and computational investigations are also described, including their tunable photophysical, redox properties, and prospective applications in sensors, molecular switches, and optoelectronic materials.

Studies of BODIPY‐ferrocene conjugates using different linkers and their applications.

1. Introduction

The development of advanced functional materials primarily depends on the efficient control of electron‐transfer (ET) reactions across various applications, such as catalysis, sensing, and optoelectronics [1]. For a long time, research has focused on inorganic metal complexes; however, recent investigations have shifted toward redox‐active organic materials (ROMs), which offer greater structural tunability and synthetic versatility [2, 3]. In this context, fluorescent dyes exhibit a significant opportunity by integrating optical signaling with electrochemical control, facilitating the development of responsive systems for molecular electronics, sensors, and switches [4, 5]. Boron(III) difluoro dipyrromethene (BODIPY), an important class of fluorescent dyes, has attracted significant interest for its excellent photophysical properties and photostability under different environmental conditions (Chart 1) [6, 7, 8, 9]. Along with its interesting optical properties, the synthetic flexibility and modifications at meso‐ and α/β‐pyrrolic positions make BODIPY an ideal skeleton for designing an advanced framework with tailored electronic/optical responses [10, 11, 12, 13, 14].

CHART 1.

Structure and IUPAC numbering of the boron dipyrrin (BODIPY), frameworks. The 3,5‐positions of BODIPY are commonly specified by ‘α’, whereas the 1,7‐ and 2,6‐positions are referred to as the β‐positions. The 8‐position is often called the meso‐position. Common boron dipyrrins have two fluorine atoms bound to the boron atom (4‐position) (as in unsubstituted 4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene, BODIPY).

The strategic incorporation of redox‐active moieties into fluorescent structures to generate multifunctional donor–acceptor (D–A) systems with adjustable optical and electronic properties. Ferrocene (Fc) is a promising redox‐active unit due to its excellent chemical stability and highly reversible one‐electron redox process (Fc/Fc⁺) with distinguished standard potential of E _1/2 = 0.403 V (vs. SCE) [15]. Covalent conjugation of ferrocene to BODIPY results in advanced hybrid systems that exhibit effective intramolecular electronic communication, mainly via photoinduced electron transfer (PET) from the ferrocene donor Highest Occupied Molecular Orbital (HOMO) ≈ −5.0 eV to the BODIPY acceptor owest Unoccupied Molecular Orbital (LUMO) ≈ −2.5 eV [1, 16]. Such processes affect fluorescence emission and excited‐state dynamics, often resulting in more than 95% fluorescence quenching in the neutral state. Importantly, this feature is of great interest because it facilitates the direct coupling between fluorescence signaling and redox control, an accomplishment that is difficult to perform with other fluorophores. These conjugates are efficient D−A systems, with Fc‐mediated PET efficiently quenching the BODIPY singlet fluorescence, and oxidation of Fc to Fc⁺ inhibits this quenching and restores emission. Fc effectively inhibits BODIPY triplet excited states via two competitive pathways: PET and triplet−triplet energy transfer (TTET) [4, 6, 7, 8]. The ability to manage both singlet (S₁) and triplet (T₁) excited‐state dynamics opens the door to the development of molecular switches, memory devices, chemical or biological sensors and other applications [7, 8, 17, 18, 19, 20].

Comprehensive spectroscopic and electrochemical investigations have yielded a significant understanding of the complex behaviour of these conjugates [6, 7, 8, 9]. The nature, length, and extent of conjugation within π‐linkers significantly influence the ability of intramolecular charge transfer (ICT) between BODIPY and ferrocene [21]. π‐Conjugated bridges, including ethynyl, vinyl, styryl, and triazole linkers, have been studied to influence charge‐transfer interactions and photophysical reactions. These structural modifications influence the electronic properties, resulting in changes to absorption and emission bands as well as to electrochemical potentials [10, 11, 12, 13, 14, 22].

BODIPY‐ferrocene conjugates have been synthesized using a variety of synthetic approaches, like Palladium‐catalyzed cross‐coupling reactions (Sonogashira and Suzuki–Miyaura), Knoevenagel condensation, Boronic acid coupling, and Copper‐catalyzed azide‐alkyne cycloaddition (click chemistry) [4, 11, 12, 22, 23]. The rapidly increasing literature remains dispersed in various research fields because of these advancements, highlighting the need for a systematic overview of the structural design strategies and redox behaviour of BODIPY‐ferrocene conjugates.

This review bridges a significant gap by summarizing reported strategies for synthesizing BODIPY‐ferrocene conjugates and discussing their spectroscopic, electrochemical, and photophysical properties. The relationship between substitution pattern, conjugation length, and electronic communication within these hybrid systems has been thoroughly investigated. Their potential applications in sensing, molecular switching, optoelectronic materials, and related functional devices are further illustrated by selected representative examples.

2. Meso‐Ferrocenyl‐BODIPY Conjugate

To begin the discussion with BODIPY‐ferrocene adducts, meso‐BODIPY‐ferrocene with alkyl groups in α‐ and β‐ positions are considered first. As shown in Scheme 1, Chen and coworkers developed spectroscopic D–A BODIPY probes 4 and 5 by integrating a strong electron donor, ferrocene, with ferrocene aldehyde 3 as a quencher unit, using 2,4‐dimethylpyrrole 1 and 3‐ethyl‐2,4‐dimethylpyrrole 2, respectively [24]. BODIPY fluorophores 4 and 5 were used to detect reactive oxygen species (ROS). This observation strongly suggests that probes 4 and 5 are highly sensitive, redox‐active, or photolabile molecules whose structural integrity and electronic state are significantly altered upon reaction with water, leading to the observed changes in color and fluorescence. Detailed experiments demonstrated that this reaction removes a cyclopentadiene ring and iron(II) from the ferrocene group, producing a BODIPY derivative 6 that retains one cyclopentadiene ring and exhibits over 100‐fold increase in fluorescence. The fluorescence enhancement is directly proportional to the amount of water present in micrograms. The authors claimed that both light irradiation and water were essential for this reaction to proceed, making the system not only sensitive to water detection but also suitable for creating an AND logic gate due to its dual‐input requirement (light and water). Above all, the current moderate dissociation reaction could provide new information about the stability of ferrocene and its derivatives.

SCHEME 1.

Synthetic scheme for donor–acceptor BODIPY probes 4 and 5.

3. BODIPY‐Ferrocene Conjugate With meso‐Heteroatom (N or O) Linker

In the earlier examples, ferrocene was directly attached to the BODIPY core. It will be interesting to study the effect of inserting a linker while maintaining ferrocene conjugation to the BODIPY core. Following a similar approach, Misra and coworkers synthesized a series of ferrocenyl BODIPY compounds 7–10 linked via a heteroatom (N or O) at the 8‐ (meso)‐position, under basic conditions [25]. The synthesis was achieved through a nucleophilic aromatic substitution (SNAr) reaction of 8‐chloro BODIPY 11 with ferrocenyl anilines 12 and 13 and ferrocenyl phenols 14 and 15 in the presence of triethylamine and K₂CO₃respectively [25]. The optical, electrochemical, and thermal characteristics of the resulting BODIPYs 7–10 are significantly influenced by the nature of the heteroatom.

For instance, the absorption spectra of BODIPYs 7 and 8 with an N‐ atom at the meso‐position show a hypsochromic shift of 80 nm, whereas BODIPYs 9 and 10 containing an O‐atom at the 8‐position display a smaller hypsochromic shift of 50 nm in comparison with 8‐chloro BODIPY 11. The ferrocenyl group has a negligible effect on the electronic absorption. The heteroatom‐linked BODIPY‐ferrocene dyads 7–10 were found to be nonfluorescent. As thermal stability is a critical criterion for the optoelectronic applications of any material, compounds 7–10 (Scheme 2) were reported to possess strong thermal stability up to 275°C, lower than the meso alkynylated ferrocenyl BODIPYs, which exhibited thermal stability up to 400°C. Hence, replacement at the 8‐position via a heteroatom reduces the thermal stability of BODIPY. Density Functional Theory (DFT) computations of dyads 7–10 suggested substantial D–A interactions. The nature of the heteroatom was found to perturb the LUMO energy level but had a negligible effect on the HOMO energy level. Single‐crystal x‐ray analysis revealed interesting supramolecular structures for the compounds. The dyad 7 formed a complex 3D structural motif with two molecules per asymmetric unit. The dyad 8 formed a 2D structural sheet with a staircase‐shaped arrangement of tetramers. The dyad 9 formed a zigzag sheet arrangement, while 10 formed a sheet with alternating bands of ferrocenyl and BODIPY units.

SCHEME 2.

Synthesis of the 8‐N and 8‐O‐connected ferrocenyl BODIPYs 7 ‐ 8 and 9 ‐10.

4. BODIPY‐Ferrocene Conjugates Using Sonogashira Coupling Reactions

Another alternative of a single‐atom linker between BODIPY and ferrocene would be C─C, C═C, C≡C and their isosteres. In alignment with this idea, Ravikanth et al. have synthesized four BODIPY‐ferrocene conjugates 16–18 using Sonogashira coupling where one or two ferrocenyl groups were covalently connected either directly to BODIPY core or to meso‐phenyl group of BODIPY [12]. The BODIPY‐ferrocene conjugates 16–18 were prepared by adopting different synthetic routes, where ethynyl ferrocene 19 [26] reacts with halogen‐substituted BODIPYs 20–22 under Sonogashira cross‐coupling reaction (Scheme 3). Conjugates were identified to be non‐fluorescent due to electron transfer from ferrocene to the boron‐dipyrromethene unit, based on spectral, electrochemical data (Table 1), and photophysical characteristics. However, when ferrocene was oxidized to ferrocenium ion with an oxidizing agent, Iron (II) perchlorate (FeClO₄), the conjugates exhibited fluorescence with decent quantum yields (0.17–0.31) and lifetimes (3.8–5.2 ns).

SCHEME 3.

Synthesis of the BODIPY‐ferrocene conjugates 16–18 with ethynyl bridge.

TABLE 1.

Photophysical characteristics and electrochemical data of BODIPY‐ferrocene conjugates discussed in the review.

Compound	λabs1 (nm) a	λabs2 (nm) a	λabs3 (nm) a	λabs4 (nm) a	Eox (V)/Ered(V) b	Refs.
7	330	418			1.06 (irr), 0.06, –1.19 (irr), –1.39 (irr)	[25]
8	330	419			1.12 (irr), 0.03, –1.21 (irr), –1.39 (irr)	[25]
9	330	455			1.07 (irr), 0.06, –1.14 (irr), –1.25 (irr)	[25]
10	330	455			1.12 (irr), 0.10, –1.24 (irr), –1.28 (irr)	[25]
16	505				0.62, −0.71b	[12]
17	531	613			1.57, 0.64, −0.74b	[12]
18	558	680			1.36, 0.64, −0.70b	[12]
23	530	610			0.70, −0.75	[23]
24	554	646			0.65, −0.62	[23]
25	561	668			0.66, −0.57	[23]
26	570	690			0.65, −0.54	[23]
33	498				1.16, 0.52, −1.24c	[14]
34	498				1.13, 0.41, −1.33c	[14]
37	538				1.03, 0.25, −1.01, −1.28c	[28]
38	546				1.11, 0.07, −0.93, −1.32c	[28]
39	544				1.09, 0.08, −0.95, −1.34c	[28]
40	440	550	571		1.12 (irr), 0.11, –0.94 (irr), –1.34 (irr)	[28]
44	405	583			1.24 (irr), 0.53, –1.05	[29]
45	340	405	590		1.21 (irr), 0.52, –1.06	[30]
46	320	405	576		1.20 (irr), 0.44, –1.08	[30]
47	350	405	586		1.21 (irr), 0.51, –1.06	[30]
50	513				—	[29]
51	523				—	[29]
52	544				—	[29]
53	543				—	[29]
56	509	656			1.56, 0.74, −0.80	[14]
57	492				0.55, –0.95	[14]
64	550	710			1.07, 0.49, 0.42, −1.06, −1.97	[11]
65	540	601			1.04, 0.44, −1.13	[11]
67	590	739			0.75, 0.13, 0.05, −1.32	[34]
69	358	575	750		1.29, 0.17, 0.02, −1.21	[35]
70	369	554	671		0.56, 0.08, −1.19	[35]
71	363	650	750		0.72, 0.31, 0.06, −1.16	[35]
74	366	613	715		0.98, 0.10, −1.04	[35]
76	654	926			0.25, 0.05, −0.80, −1.70	[39]
81	398	581			0.11, −1.07	[39]
82	652	331			0.39, 0.06, –1.32	[39]
83	586	410			0.80 (irr), 0.12, –0.96 (irr)	[39]
84	647	333			0.08, –0.10, –1.00 (irr)	[39]
85	313	651			0.09, 0.02, −0.90	[39]
92	494	810			0.21, 0.05, −1.23	[39]
93	489	818			0.13, −0.13, −1.30	[39]
102	310	350	505	518	0.97, 0.32, ‐1.50	[4]
105	360	480	504	514	0.90, 0.19 (irr), –1.53	[42]
106	390	500	538	551	1.10, 0.18 (irr), –1.30	[42]
116	567				1.28, 0.52, −0.35, −0.71‐1.32, −1.80	[21]
117	561				1.21, 0.48, −0.79, −0.88, −1.16, −1.29	[21]
118	521				1.34, 1.10, 0.40, −0.73, −1.42, −2.03, −2.23	[21]
40	551				1.12, 0.11, −0.94, −1.34	[21]
119	512				1.17, 0.10, −1.12, −1.41	[21]
134	665				0.42, −0.57, −0.99	[43]
136	665				0.50, −0.99	[43]
138	505				0.05, −1.03, −1.42, −1.61, −2.05	[43]
151					0.58, 0.27, –0.03, –1.72, –1.88	[55]

^a Measured in DCM/toluene/chloroform.

^b Recorded in benzonitrile with TBAClO₄ or DCM / 0.1 M TBAP as the support electrolyte, potentials determined versus ferrocene/ferrocenium couple.

Later, the same group reported four meso‐furyl BODIPY‐ferrocene conjugates 23–26, in which one, two and three ferrocene groups were linked directly to meso‐furyl BODIPY core by coupling of appropriate meso‐furyl and bromo meso‐furyl BODIPYs 29 and 30 with α‐ethynyl ferrocene 19 under mild Pd(0) coupling conditions prepared by two synthetic routes [23]. The absorption investigations of compounds 23–26 exhibited charge transfer bands, suggesting that the ferrocene and BODIPY moieties interact inside the conjugates. The first one‐pot synthesis of the mono‐ferrocenyl‐connected BODIPYs 23 and 24, meso‐(5‐bromo‐2‐furyl)‐dipyrromethane 27, was first oxidized with DDQ in CH₂Cl₂ at room temperature for 10 min, then treated with triethylamine, followed by BF₃.OEt₂ for 30 min afforded 29 as a dark red fluorescent solid in 26% yield. The BODIPY 30 was prepared eventually by treating 28 with one equivalent of N‐Bromo succinimide (NBS) at −78°C under nitrogen atmosphere for 1 h followed by flash silica column chromatographic purification resulted the 3‐bromo meso‐furyl dipyrromethane which on oxidation with DDQ and subsequent treatment with BF₃.OEt₂ at room temperature (Scheme 4). The BODIPY‐ferrocene conjugates 23 and 24 were prepared by coupling of 29 and 30 with α‐ethynyl ferrocene 19, respectively, in toluene/Et₃N in the presence of catalytic amounts of AsPh₃/Pd₂(dba)₃ at 50°C for 2 h (Scheme 4) in 50%–60% yield. The BODIPY‐ferrocene conjugates 25 and 26 were prepared in one pot starting with meso‐(5‐bromo‐2‐furyl)‐dipyrromethane 27 (Scheme 5) [27]. Compound 27 was treated with NBS in THF at room temperature, then oxidized with DDQ and complexed with BF₃.OEt₂ in CH₂Cl₂. The mixture of 3‐bromo‐ and 3,5‐dibromo meso‐(5‐bromofuryl)BODIPYs 31 and 32, respectively, was coupled with α‐ethynyl ferrocene 19 in toluene/Et₃N in the presence of catalytic amounts of AsPh₃/Pd₂(dba)₃ at 50°C. Purification was performed by column chromatography on silica gel, affording compound 25 in 40% yield and compound 26 in 35% yield (Scheme 5). The BODIPY‐ferrocene conjugates 23‐26 are freely soluble in common organic solvents such as CHCl₃, CH₂Cl₂.

SCHEME 4.

meso‐furyl BODIPY‐ferrocene conjugates 23 and 24.

SCHEME 5.

meso‐furyl BODIPY‐ferrocene conjugates 25 and 26.

Two novel BODIPY‐ferrocene viscosity probes 33 (with ethyne bridge ‘FcEB’) and 34 (without ethyne bridge ‘FcB’) (Scheme 6) have been synthesized by Sonogashira cross‐coupling of BODIPY 35 with ethynyl ferrocene 19 to get deep‐red needle‐shaped crystals of FcEB 33 with a moderate yield of 30%. FcB 34 was synthesized as an orange crystal in 40% yield following the conventional synthetic pathway of 3,5‐dimethyl pyrrole with ferrocene aldehyde 36 laid by Yin et al. [14]. They demonstrated that an “interlock” packing mode was observed in both FcEB 33 and FcB 34, using x‐ray diffraction data. FcEB 33 exhibits a molecular rotor property and an enhanced quantum yield in a viscous solvent. Interestingly the emission increases drastically with the viscosity. It was also established that the structural and optical characteristics can be controlled by molecular structure design and the introduction of different functional groups. This also suggests that the method has considerable potential for producing viscosity probes particularly for biological systems.

SCHEME 6.

Synthesis of a highly sensitive viscosity probe based on BODIPY‐ferrocene dyads: 33 and 34.

As shown in Scheme 7 below, meso‐alkynylated ferrocenyl BODIPYs 37–40 with varying length of conjugation have been designed by Misra and coworkers in 2013 employing a palladium‐catalyzed Sonogashira cross‐coupling reaction of meso‐chloro BODIPY 11 with the corresponding ferrocenyl ethynes 19, 41–43 [28]. The objective of linker with variable conjugation was to improve electronic communication between the donor ferrocene and the acceptor BODIPY. Here, charge transfer from ferrocene to BODIPY was affirmed by photonic and electrochemical characteristics. As expected, bathochromic shift was observed in 37–40 with increasing conjugation length from 538 nm for 37 to 551 nm for 40 (in toluene). All BODIPYs 37–40 display a broad charge transfer band between 600 and 650 nm, this band is most prominent in 37, which indicates strong electronic coupling between the donor ferrocene and the acceptor BODIPY. All 8‐alkynylated ferrocenyl BODIPYs 37–40 are very weakly fluorescent to nonfluorescent (ϕ ≤ 10⁻³).

SCHEME 7.

Synthesis of meso‐alkynylated ferrocenyl BODIPYs 37–40 using 8‐chloroBODIPY 11.

The same group synthesized diverse series of beta dialkynylated BODIPY‐ferrocene triads 44–47 by the Sonogashira cross‐coupling reaction of diiodoBODIPY 49 with the corresponding terminal alkynes 19, 41–43 (Scheme 8) [29, 30]. Here again the design objective was to improve the electronic communication between the donor ferrocene and the acceptor BODIPY by increasing the count of donor ferrocene units and conjugation on both sides of the BODIPY moiety at the beta position in comparison to Scheme 7, where the conjugation length of the linker was increased at the meso position of the BODIPY unit to study the effects.

SCHEME 8.

Synthesis of beta dialkynylated BODIPY‐ferrocene triads 44–47.

5. BODIPY‐Ferrocene Conjugates Using Suzuki and Sonogashira Reactions

A series of D–A beta monoferrocenyl substituted BODIPYs 50–53 have been designed and synthesized by Dhokale et al. via palladium‐catalyzed Suzuki and Sonogashira coupling reactions [29]. The donor group is linked to the pyrrolic position of the BODIPY in numerous examples. The authors aimed to create a D–A system 50–53 by replacing the donor group at just one β‐pyrrolic position of the BODIPY 54 [31]. The UV–vis absorption results indicate ICT from the ferrocene to the BODIPY. The fluorescence quantum yield was drastically reduced when the ferrocenyl group was directly attached to the BODIPY 54. The single‐crystal x‐ray structures of 50–53 exhibit remarkable supramolecular interactions. Authors reported the crystal structure of 50 showing an extensive hydrogen‐bonded 2D network, 51 formed a sheet‐like structure, 52 packed in a zigzag manner along the α‐axis, whereas 53 arranged in a sheet‐like structure in which both the surfaces of the sheet are covered with the ferrocenyl group. The beta mono‐ferrocenyl substituted BODIPYs 50 was synthesized by Suzuki coupling reactions of mono‐bromo BODIPY 54 with the ferrocenyl boronic acid 55. In contrast, BODIPY‐ferrocene conjugates 51–53 were synthesized by Sonogashira coupling reactions of 54 with ferrocenyl substituted ethyne 19, 41, and 42, respectively (Scheme 9). The bromo‐substituted BODIPY 54 was reacted with the ferrocenyl boronic acid 55 under the Suzuki coupling reaction conditions to yield ferrocenyl‐substituted BODIPY 50 in 45% yield. The Sonogashira coupling reaction of bromo BODIPY 54 with ethynyl ferrocene 19, 4‐ferrocenylphenylacetylene 41, and 3‐ferrocenylphenylacetylene 42 resulted in 51, 52, and 53 in 78%, 58%, and 42% yields, respectively.

SCHEME 9.

Synthesis of beta monoalkynylated BODIPY‐ferrocene dyads 50–53.

6. BODIPY‐Ferrocene Conjugates Using Knoevenagel Condensation Reactions

As mentioned earlier, another alternative for linking the ferrocenyl group to the BODIPY moiety is an isostere of a C═C bond. A series of dyads and triads using ferrocene as the donor and BODIPY as the acceptor, linked either directly 56 and 58 or through an N‐phenylmethanimine 57 and 59 or through ethynylbenzenelinker 38 and 62, was synthesized in 2017. While the directly linked dyad 56 and triad 58 were prepared through acid‐catalyzed condensation of pyrrole with ferrocenecarboxaldehye 3 and 1,1’‐ferrocenedicarboxaldehyde 3a, followed by oxidation with DDQ, respectively, the latter two imine‐linked dyad 57 and triad 59 were obtained through Schiff base condensation of amino BODIPY 60 with 3 and 1,1’‐ferrocenedicarboxaldehyde 3a in ethanol with a catalytic concentration of acetic acid. The third set of alkyne‐linked dyads 38 and 62 were prepared by Sonogashira coupling reactions, respectively, using CuI, Cs₂CO₃, and PdCl₂(PPh₃)₂ in toluene as solvent (Scheme 10) [32, 33]. The compounds were fully characterized with spectroscopic data and single‐crystal x‐ray analysis in one case. The peaks corresponding to the Fe(II)/Fe(III) redox couple at 0.33 to 0.38 V showed a varying degree of positive anodic shift, which reflected the strong electron‐withdrawing effect of the corresponding BODIPY unit. Correlating the linear optical data, electrochemistry, theoretical calculations and highest second order polarizability (β), it was established that the chromophores with the BODIPY unit directly attached to ferrocene, show the highest second order polarizability (β) value, which is attributed to MLCT bands in the absorption spectrum of 56 and 58, which are absent in the other chromophores, where the donor ferrocene is attached to the acceptor via imine linkers 57 and 59 and alkyne linker 38 and 62. Due to electron transfer from the ferrocene to the BODIPY unit, these compounds 57 and 59 are naturally non‐fluorescent. However, when an oxidizing agent oxidizes ferrocene to the ferrocenium ion, the electron‐transfer process is terminated, thereby increasing fluorescence. This tendency is not found in compounds 38 and 62, where the linker is dominant over ferrocene as the donor, as anticipated by the NBO calculations. The electrochemical studies demonstrated a more anodic shift in the oxidation peak of ferrocene in compounds 56 and 58 compared to other chromophores, in which the donor Fc is attached to the acceptor via imine/alkyne linkers. Indicating a strong electronic communication between the ferrocene and the BODIPY unit, which was further supported by NBO calculations. The authors reported in this investigation that these chromophores exhibited second‐order nonlinear polarizabilities comparable to those previously reported.

SCHEME 10.

Synthesis of BODIPY‐ferrocene dyads 38, 56 and 57, 62 and triads 58 and 59.

Singh and coworkers also reported the synthesis of a novel D–A ferrocenyl imine substituted BODIPY‐ferrocene dyad 57 using a one‐pot acid‐catalyzed Knoevenagel condensation between ferrocene‐1‐carboxaldehyde 3 and a BODIPY amine 60, which was prepared by reduction of nitro BODIPY 63 (Scheme 11) [32]. Dyad 57 exhibited unique photophysical properties and serves as a turn‐on fluorogenic chemosensor for Hg²⁺ and a chemodosimeter for Cr³⁺ ions. The photophysical study revealed that compound 57 has a weak emission band at 507 nm. This poor emission was attributed to a PET process from the strong donor ferrocenyl‐imine unit to the strong acceptor BODIPY core. The ion‐sensing behavior of compound 57 showed that upon addition of Hg²⁺ (in the concentration range 2.85 × 10⁻⁶ to 3.33 × 10⁻⁴ M, as perchlorate salt in H₂O), a bathochromic shift in the emission from 507 nm to 520 nm is observed, accomplished by a stepwise increase in intensity. This was interpreted as a restriction of PET. On addition of Cr³⁺ (2.85 × 10⁻⁶ to 5.0 × 10⁻⁴ M, as perchlorate salt in H₂O), only the emission intensity at 507 nm increases; no bathochromic shift was noted. The fluorescence response was reversed with EDTA in the case of Hg²⁺ sensing, confirmed reversible coordination. However, in Cr³⁺ sensing, this reversibility was absent, suggesting chemodosimetric operation. The sensor was selective for Hg²⁺ and Cr³⁺ ions among a variety of metal ions (Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ba²⁺, Ni²⁺, Mn²⁺, Co²⁺, Cu²⁺, Zn²⁺, Pb²⁺, Fe³⁺, Al³⁺, Yb³⁺, La³⁺, Sm³⁺, Lu³⁺, Ce³⁺, Pr³⁺, Tb³⁺, Nb³⁺, and Nd³⁺), showing little or no response to the others. This study highlights the utility of BODIPY‐ferrocene dyad 57 for selective metal ion recognition via controlled PET processes and fluorescence modulation in response to specific ions.

SCHEME 11.

Synthesis of BODIPY‐ferrocene dyad 57.

Electrochromism based on the charge transfer process in a BODIPY‐ferrocene D–A molecule diFc‐BODIPY triad 64 and BODIPY‐ferrocene dyad 65 were synthesized using ferrocene aldehyde 3 and BODIPY 35 in the presence of toluene, glacial acetic acid, piperidine and Mg(ClO₄)₂ by Zhu et al. Authors explored the characteristic BODIPYs 64‐65 by NMR spectra, photophysical properties, and electrochemical properties (Scheme 12) [11].

SCHEME 12.

Synthesis of BODIPY‐ferrocene triad 64 and dyad 65.

Galangau and Miomandre et al. synthesized the BODIPY‐ferrocene conjugate 67 in 2013 [34]. Piperidine was added to a solution of BODIPY 66 in toluene, under an argon atmosphere, followed by ferrocenecarboxaldehyde 3 in toluene. For about 30 h, the resultant mixture was refluxed. An ICT from the donor ferrocene to the acceptor BODIPY has been predicted theoretically and experimentally validated, leading to effective fluorescence suppression of dyad 66 in its neutral state. Fluorescence can be triggered by oxidizing both ferrocene units either chemically or electrochemically. The authors reported that a fully reversible fluorescence switch is evidenced by coupling total internal reflection fluorescence (TIRF) microscopy with electrolysis in an electrochemical cell using the dye Alexa Fluor 647 (AF647). The fluorescence was observed at the single‐molecule level on an indium tin oxide (ITO) electrode surface (Scheme 13).

SCHEME 13.

Synthesis of diFc‐BODIPY triad 67.

Zatsikha and Nemykin et al. reported D–A complexes 69–71, as shown in Scheme 14 [35]. A series of mono and diferrocene‐substituted D–A dyads and triads 69–71 were synthesized by stepwise modification of the methyl groups at the α positions of BODIPY 68, resulting in the organometallic substituents being fully conjugated with the BODIPY π system. Knoevenagel condensation of dimethyl BODIPY 68 with ferrocene aldehyde 3 was used to create diferrocene‐containing BODIPY 69 [35]. High reactivity of the methyl groups at α positions of dimethyl‐containing BODIPY 68 was exploited for preparing a series of mono‐ferrocene substituted D–A dyads 70, 71, 74, and diferrocene substituted triad 69, respectively. In these dyads and triads, organometallic substituents are fully conjugated with the BODIPY π system. All D–A complexes 69–71 have strong absorption in the NIR region and quenched steady‐state fluorescence, which can be partially restored upon oxidation of organometallic groups. A simple approach to modify the BODIPY nucleus was developed by the same authors. The method is based on the reaction of acetaldehyde‐substituted dye with primary amines, followed by cyclization of the resulting enamine. This procedure allowed the preparation of a series of new BODIPY derivatives with functional substituents useful for various practical purposes, including bioconjugation and other biomedical applications. The synthesized BODIPY 73 annealed to a pyridone fragment are stable compounds and intense fluorophores with the emission maximum around 615 nm, [36] which is slightly red‐shifted, probably by the introduction of styryl substituent. Pyridone BODIPY‐ferrocene conjugate 74 was assembled by reaction of pyridone BODIPY 73 with ferrocenecarboxaldehyde 3, piperidine, and acetic acid in refluxing toluene for 1 h (Scheme 14).

SCHEME 14.

Synthetic pathways for preparation of organometallic BODIPYs 69‐71 and 74.

To obtain a BODIPY‐ferrocene conjugate with an intense NIR MLCT band, BODIPY 68 was treated with potassium cyanide in the presence of crown ether (Scheme 15). This reaction led to the formation of the colorless anionic adduct 75, which was further oxidized with lead(IV) acetate to meso‐cyano‐BODIPY 76 [37, 38]. Finally, meso‐cyanoBODIPY 76 was converted into meso‐cyano diferrocene‐containing BODIPY 77 by a standard Knoevenagel condensation with ferrocenecarbaldehyde 3. The UV–vis–NIR spectrum of meso‐cyano diferrocene BODIPY 77 was shifted to the low energy compared to UV–vis–NIR spectrum of the reported earlier spectrum of diferrocenyl BODIPY 69, which lacks a cyano group in the meso‐position. In fact, 76 exhibited a large MLCT and a comparatively narrow π–π* band at 926 and 654 nm, respectively, whereas non‐cyano containing BODIPY 69 exhibited similar bands at 752 and 575 nm.

SCHEME 15.

Synthetic pathways for preparation of meso‐cyano diferrocenyl BODIPY 77.

The Fc‐BODIPY 77 was characterized by various spectroscopic, electrochemical, and theoretical techniques. Interestingly, UV–vis–NIR spectrum had a striking similarity with that of previously reported magnesium 2(3),7(8),12(13),17(18)‐tetracyano‐3(2),8(7),13(12),18(17) tetraferrocenyl‐5,10,15,20‐tetraazaporphyrin P1 (Chart 2). Similarly, the UV–vis–NIR spectra of BODIPY 69 closely resembles to the UV–vis–NIR spectra of magnesium 2(3),7(8),12(13),17(18)‐tetraferrocenyl‐5,10,15,20 tetraazaporphyrin P2 respectively (Chart 2) [37, 38].

CHART 2.

Structure of magnesium porphyrins P1 and P2.

Zatsikha and Nemykin et al. reported the synthesis of mono‐ and di‐N‐ferrocenyl 2‐pyridone BODIPY‐conjugates 81 and 85 as outlined in Scheme 16. First, ferrocene‐enamine compound 80 was prepared by reacting BODIPY 78 and aminoferrocene 79 [39]. This ferrocene‐enamine 80 undergoes an intramolecular cyclization in DMF with the formation of mono (ferrocenyl)‐containing BODIPY 81 [36]. BODIPY 81 can then be converted into enamine 82, which undergoes acidolysis with acetic acid to form BODIPY aldehyde 83. This aldehyde can be transformed into di‐(ferrocenyl)‐containing enamine 84, which then undergoes intramolecular cyclization to form a target di‐N‐ferrocenyl 2‐pyridone BODIPY‐conjugates 85 [36]. Structures of BODIPYs 80‐85 were confirmed by ¹H and ¹³C NMR methods as well as high‐resolution mass spectrometry. UV–vis spectra of the target BODIPYs 81 and 85 associated with the BODIPY core show that the low‐energy π–π* transition undergoes a redshift from 552 nm in 78 to 581 nm in 82 and 651 nm in 85. This is indicative of conjugation of the 2‐pyridone fragment into the π‐system of the BODPY chromophore. It is interesting that, unlike the earlier reported BODIPY‐ferrocene conjugates with ferrocene groups attached to the BODIPY core via α‐vinyl linkers [14], UV–vis spectra of BODIPYs 81 and 85 have no broad and intense metal‐to‐ligand charge‐transfer (MLCT) band in the NIR region. Misra and coworkers reported a similar situation for several BODIPY‐ferrocene conjugates [28, 30]. The low‐energy band in BODIPYs 81 and 85 is slightly broadened compared to the same band in standard BODIPY compounds, which might be indicative of overlap between MLCT and π–π* bands in 81 and 85. Alternatively, the intensity of the MLCT band in BODIPYs 81 and 85 could be below and thus, difficult to observe if its energy is close to that of the BODIPY‐centered π–π* transitions. UV–vis spectra of the BODIPY intermediates 80, 82, 83, and 84 correlate well with the trend observed for the target BODIPYs 81 and 85. For instance, a major absorption peak at 592 nm in 80 is close to that in 81 (581 nm). BODIPYs with more extended π‐systems (82, 83, and 84) have a major absorption band between 651 and 652 nm, which is indistinguishable from that observed in 85 (651 nm). More importantly, the presence of the ferrocene fragment is clearly seen in intermediates 80, 82, 83, and 84. The UV–vis spectra of all these compounds have clear, broad, and intense MLCT bands, which are close in energy to the major π–π* transition.

SCHEME 16.

Synthetic pathways for preparation of mono‐ and di‐N‐ferrocenyl 2‐pyridone BODIPYs 81 and 85.

BODIPY‐merocyanine dyads 92 and 93 were generated by a sequence of Knoevenagel condensation events involving asymmetric acetal 86 and ferrocene carboxaldehyde 3, leading to the creation of BODIPY‐ferrocene dyad 87, which, on hydrolysis, yields aldehyde 88 as indicated in Scheme 17 [40]. Aldehyde 88 can be transformed to reactive enol acetate intermediate 89, which, upon condensation with N‐methyl heterocyclic quaternary ammonium salts 90 and 91, results in the formation of the target DAD BODIPY‐ferrocene‐merocyanine systems 92 and 93. The spectroscopic signatures of the BODIPY‐ferrocene‐merocyanines 92 and 93 were studied by a variety of methods. Their high‐resolution atmospheric pressure chemical ionization (APCI) mass spectra were consistent with the proposed composition, while NMR spectra clearly indicated the presence of polymethine chain fragments in 92 and 93, as well as the asymmetric nature of these systems. The UV–vis NIR spectra of BODIPY‐ferrocene‐merocyanine dyads 92 and 93 are similar to each other but are rather unusual compared with the earlier reported BODIPY‐ferrocene systems with compound 26 and the FcCH = CHBODIPY architecture [23, 34]. They are dominated by a broad asymmetric band in the NIR region observed at ∼800 nm with higher‐energy shoulder around 650 nm.

SCHEME 17.

Synthetic pathways for BODIPY‐ferrocene‐merocyanines dyads 92 and 93.

7. BODIPY‐Ferrocene Conjugates Using Copper‐Catalyzed Azide‐Alkyne Cycloaddition

Pavlov and coworkers demonstrated that the copper‐catalyzed azide‐alkyne cycloaddition of BODIPY acetylene derivative 94 and ferrocene azides 95 and 96 in supercritical CO₂ at 80°C and 81 bar pressure produces high yields of the corresponding triazole‐containing BODIPY‐ferrocene conjugates 97 and 98 (Scheme 18) [41].

SCHEME 18.

Synthesis of triazole‐containing BODIPY‐ferrocene conjugates 97 and 98.

Three distinct BODIPY‐ferrocene dyads 33, 103, and 104 with various linkers between the BODIPY and the ferrocene moieties were produced by Wu et al. for studying reversible electrochemical switching of the singlet excited‐state fluorescence and triplet excited states of BODIPY [4]. BODIPY‐ferrocene dyads 33 were prepared by reacting alkyne BODIPY 100 with iodoferrocene 99 under Sonogashira cross‐coupling reaction. BODIPY‐ferrocene dyads 103 and 104 were prepared by reacting ethynyl ferrocene 19 with azide BODIPYs 101 and 102 under click reaction conditions using copper sulphate and sodium ascorbate under THF/Water solvent (Scheme 19). The photophysical properties of the dyads 33, 103, and 104 were examined utilizing steady‐state UV–vis absorption spectroscopy, fluorescence, electrochemical characterization (Table 1), time‐resolved fluorescence, and nanosecond transient absorption spectroscopies. The fluorescence of the BODIPY moieties in the dyads was quenched by the PET. This conclusion was supported by electrochemical characterization and computation of the Gibbs free energy changes of PET. The authors demonstrated that the fluorescence of the BODIPY moiety may be reversibly turned ON and OFF by electrochemical oxidation of the ferrocene moiety (Fc/Fc⁺). It was shown that the ferrocene moiety is efficient at quenching the triplet excited states of BODIPYs. Both PET and TTET quenching mechanisms, were responsible for the intramolecular and intermolecular quenching of the triplet excited states of the diiodoBODIPY unit 102. These BODIPY‐ferrocene dyads were used to achieve reversible electrochemical switching of the fluorescence of the BODIPY fluorophore, while quenching of the triplet excited state of BODIPY by ferrocene was also investigated (Scheme 19).

SCHEME 19.

Synthesis of alkyne bridged 33 and triazole bridged BODIPY‐ferrocene dyads 103 and 104.

Shi and coworkers, developed an efficient BODIPY‐ferrocene based dark quencher and utilized it to construct a Förster Resonance Energy Transfer (FRET)‐based fluorescent probe featuring a biotin moiety for targeting cancer cells for diagnostic purposes, along with a glutathione‐cleavable disulfide linker connecting the quencher to a distyryl BODIPY fluorophore [42]. The synthesis approach for this probe 114a, and its non‐cleavable analogue 114b as a control molecule was based on Knoevenagel condensation of monostyryl BODIPY 105 with one equiv. of ferrocene aldehyde 3 gave distyryl BODIPY 106 and with p‐hydroxybenzaldehyde yielded distyryl BODIPY 107 (Scheme 20a). This compound 107 was then coupled with biotin 108 in the presence of 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and 4‐(dimethylamino)pyridine (DMAP) to give the biotin conjugate 109 (Scheme 20a).

SCHEME 20.

(a) Synthesis of BODIPY biotin conjugate 109. (b) Synthesis of fluorescent probe 114a and the non‐cleavable compound 114b.

To generate the quenching component, previously described ferrocenyl BODIPY 110 [43] was alkylated with propargyl bromide to yield the alkynyl analogue 111. Subsequently, click reaction of 111 with an excess of diazide 112a and 112b to afford the corresponding monoazide 113a and 113b, respectively.

The BODIPY biotin conjugate 109 and corresponding monoazide 113a and 113b were conjugated under click reaction conditions to obtain the target fluorescent probe 114a and the non‐cleavable control compound 114b, as shown in Scheme 20b.

The fluorescence of probe 114a is quenched in its native state via FRET and ICT due to the presence of the ferrocenyl unit. However, upon encounter with glutathione, either in phosphate‐buffered saline or inside cancer cells, the disulfide bond cleaves, thereby dissociating the fluorophore from the quencher and resulting in a significant increase in fluorescence emission. According to flow cytometry studies, this probe further demonstrated uptake by A549 human lung adenocarcinoma epithelial cells, which express biotin receptors, compared with CHO‐K1 cells used as a negative control. Since both biotin receptors and glutathione levels are commonly overexpressed in cancer cells, this dual‐functional fluorescent probe 114a holds great promise for selective cancer imaging applications.

8. BODIPY‐Ferrocene Conjugate Using [2 + 2] Cycloaddition‐Retro‐Cyclization

To understand the effect of substitution on C–C linkage, Dhokale et al. reported BODIPY‐ferrocene conjugates 116‐118, demonstrating the [2 + 2] cycloaddition‐retro‐cyclization to be an efficient route, especially for alkyne groups surrounded by electron‐rich groups [21]. Due to the steric hindrance existing groups around the triple bond in BODIPY‐ferrocene conjugate 116 and its electron‐deficiency resulting from the simultaneous presence of both the BODIPY and the 1,1,4,4‐tetracyanobuta‐1,3‐diene (TCBD) unit, BODIPY‐ferrocene conjugate 117 could not undergo cycloaddition retro‐electrocyclization reaction. In BODIPY 116, the ferrocenyl group maintains the electron density at the alkyne unit against the electron‐withdrawing BODIPY moiety, whereas in BODIPY 117, both the BODIPY and TCBD withdraw the electron density from the alkyne unit, making it electron‐deficient and inert toward the [2+2] cycloaddition‐retro electrocyclization reaction.

The reaction between an electron‐rich alkyne and tetracyanoethylene (TCNE) to form a TCBD structure occurs through a two‐step sequence: a [2+2] cycloaddition followed by a rapid retro‐electrocyclization reaction. This is often referred to as the “CA‐RE” click reaction. BODIPY‐ferrocene conjugates 116 and 117 could be obtained by mixing TCNE 115 and the corresponding BODIPY‐ferrocene conjugates 37 and 40 in a 1:1 ratio, at 40°C for 2 and 8 h, respectively. BODIPY 119 [44] could undergo a similar transformation, furnishing the targeted BODIPY‐ferrocene conjugate 118 after 7 days. The significant difference in reaction times (hours vs. days) is due to differences in the electronic and steric properties of the starting materials, which affect the reaction rate (Scheme 21).

SCHEME 21.

Synthesis of BODIPYs 116‐118 resulting from the [2+2] cycloaddition‐retro‐cyclization with TCNE 115.

The incorporation of the TCBD unit strongly changes the properties, inducing a significant red shift in the S₀→S₁ absorption band (e.g., 29 nm for 117) compared to their precursors, despite potential conjugation disturbance. The S₀→S₂ band in these derivatives shows a blue shift and increased intensity. The CT band seen in 116 merges into the broadened S₀→S₁ absorption band of 118. Notably, all TCBD‐substituted ferrocenyl BODIPYs 116‐118 are non‐emissive.

9. BODIPY‐Ferrocene Conjugates Using Long Chain Linkage

Yuan and coworkers in 2024 showed that PDT can kill tumor cells by generating singlet oxygen (¹O₂) under light irradiation, but this effect is limited by hypoxia in neoplastic tissue [45]. Chemodynamic therapy (CDT) can generate toxic hydroxyl radicals (*OH) to eradicate tumor cells via the catalytic decomposition of endogenous hydrogen peroxide (H₂O₂), and its therapeutic effect is highly dependent on the concentration of H₂O₂. Authors prepared a BODIPY‐ferrocene conjugate 121 using BODIPY 120 with N, N‐dimethylferrocenylamine in DCM for 3 h stirring at ambient temperature. BODIPY‐ferrocene conjugate 121 has a balanced ¹O₂ and *OH generation capacity, which can serve as a high‐efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as‐prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficacy can be achieved upon light irradiation. Compared with PDT or CDT monotherapy, the BODIPY‐ferrocene conjugates can significantly increase intracellular ROS levels in tumor cells after light irradiation, thereby inducing tumor cell apoptosis at low drug doses. In this way, a synergistic anti‐tumor treatment is achieved by combining PDT and CDT (Scheme 22).

SCHEME 22.

Synthetic route for BODIPY‐ferrocene conjugate 121.

Julie Pham and coworkers studied the synthesis and characterization of a novel BODIPY‐ferrocene dyad 125 [46]. The dyad featured BODIPY and ferrocene units linked by an ethynyl styryl linker. The synthesis of ethoxy silane‐functionalized molecular targets as BODIPY‐ferrocene conjugate 125 is presented in Scheme 23. BODIPY‐ferrocene conjugate 124 functionalized in the meso position by a triethoxysilane terminated chain for future immobilization, while compound 125 bears ferrocenylethynylstyryl units at the α‐position. Briefly, BODIPY 124 was prepared using a classical three‐step one‐pot approach from BODIPY 122 [47]. The ferrocene units were grafted at the α‐position of the BODIPY core through a Knoevenagel condensation of BODIPY 122 with 4‐[(ferrocene)ethynylbenzaldehyde] 123 in the presence of piperidine in acetonitrile at 100°C for 12 h and afforded the α‐bis‐ferrocenyl ethynylstyryl‐BODIPY 124. This derivative was then reacted with 3‐(triethoxysilyl)propyl isocyanate and diisopropylethylamine (DIPEA) in DCM at 40°C for 4 days to yield the siloxane precursor BODIPY 125. They explored its fluorescence, electrochemical, and electrofluorochromic properties, initially in solution and subsequently as a surface‐confined species. The siloxane precursor BODIPY 125 was covalently grafted onto an indium tin oxide (ITO) surface by a siloxane derivatization at the meso position of the BODIPY unit. The resulting monolayer exhibited high stability and positive electrofluorochromism. Fluorescence was effectively “switched on” upon oxidation and monitored electrochemically, demonstrating good reversibility over multiple cycles.

SCHEME 23.

Synthesis of BODIPY‐Ferrocene Conjugate 125.

Jiang et al. reported that dicarboxy distyryl BODIPY 126 core was conjugated to two ferrocenyl quenchers through acid‐labile ketal and/or thiol‐cleavable disulfide linkers, of which the fluorescence and photosensitizing properties were significantly quenched through a PET process [48]. Authors reported dicarboxy distyryl BODIPY 126 on reaction with the disulfide‐, ketal‐ and ethylene‐linked ferrocene derivatives 127a‐c (Scheme 24a) in the presence of EDC·HCl and DMAP. The derivatives were transformed to corresponding pH‐responsive photosensitizer 128, thiol‐sensitive counterpart 129, and the non‐cleavable analogue 130, respectively, in satisfactory yield. To prepare the dual activable analogue 128‐130, dicarboxy distyryl BODIPY 126 was treated with equimolar amounts of 127a, 127b, and 127c under the same reaction conditions (Scheme 24a). The unsymmetrical distyryl BODIPY 131 was synthesized in 11% yield by reacting dicarboxy distyryl BODIPY 126 with disulfide‐ and ketal‐linked ferrocene derivatives 127a and 127b, respectively (Scheme 24b).

SCHEME 24.

(a) Synthesis of symmetrical BODIPY‐ferrocene Conjugates 128–130 with the disulfide‐, ketal‐ and ethylene‐linker. (b) Synthesis of unsymmetrical BODIPY‐ferrocene Conjugate 131.

The two symmetrical BODIPY analogues 128 that contained disulfide linkers and 129 that contained the ketal linker could only be activated by a single stimulus, whereas the unsymmetrical BODIPY analogue 131 was responsive to dual stimuli. Upon reaction with acid and/or dithiothreitol (DTT), these linkers were selectively cleaved. The separation of the BODIPY core and the ferrocenyl moieties restored the photoactivities of the former in phosphate‐buffered saline and inside the MCF‐7 breast cancer cells, rendering these compounds as potential activable photosensitizers for targeted photodynamic therapy. The dual activable analogue exhibited the greatest enhancement in intracellular fluorescence intensity in both an acidic environment (pH 5) and the presence of DTT (4 mm). Its photocytotoxicity against MCF‐7 cells also increased by twofold upon preincubation with 4 mm of DTT. Activation of this compound was further validated in nude mice bearing an HT29 human colorectal carcinoma. A significant increase in fluorescence intensity in the tumor was observed over 9 h after intratumoral injection.

10. BODIPY‐Ferrocene‐Fullerene Conjugates

The comprehensive studies on ferrocene‐BODIPY and fullerene‐BODIPY conjugates offer a strong rationale for exploring triads integrating all three frameworks. Over the last 25 years, research on fullerenes has been dedicated to understanding the way to produce stable, well‐characterized and highly soluble fullerene derivatives, which retain the original properties of C₆₀. Applications across a wide range of fields, especially in new materials design, have enriched the literature with fascinating examples in which fullerenes are directly involved [49]. A distyryl BODIPY‐ferrocene dyad 135 and a distyryl BODIPY‐ferrocene‐C₆₀ triad 136, known as highly efficient, heavy‐atom‐free photosensitizers which can be used in PDT and photocatalysis were synthesized by Knoevenagel condensation reaction [43]. Scheme 25 shows the synthetic route used to prepare these distyryl BODIPY (DSBODIPY) based arrays. Condensation of monostyryl BODIPY 132 [50], on treatment with ferrocenecarboxaldehyde 3 in the presence of piperidine and acetic acid condition, led to the formation of Fc‐DSBODIPY dyad 133. Compound 133 was further treated with 1,3‐dibromopropane, K₂CO₃ in DMF to yield bromoethane‐substituted Fc‐DSBODIPY dyad 134, and it was later reacted with 4‐hydroxybenzaldehyde in the presence of K₂CO₃ to afford aldehyde‐substituted DSBODIPY‐ferrocene dyad 135. The Fc‐DSBODIPY‐C₆₀ triad 136 was prepared by treating 135 with C₆₀ and sarcosine following the Prato procedure [51]. Photoexcitation of newly synthesized DSBODIPY arrays exhibited PET, generating charge‐separated species. Their redox potential, determined by cyclic voltammetry, provided information on the direction of charge separation and the energies of these states. Femtosecond transient spectroscopic studies reveal that a fast charge separation occurs for both the DSBODIPY‐ferrocene dyad 134 and DSBODIPY‐ferrocene‐C₆₀ triad 136, but relatively slow charge recombination is observed only for the triad 136. The lifetime of the charge‐separated state is 500 ps. Charge recombination of the dyad 134 and triad 136 leads to population of the triplet excited state of ferrocene and the ground state, respectively.

SCHEME 25.

Synthesis of BODIPY‐ferrocene‐fullerene triad 136.

The synthesis of the BODIPY‐ferrocene‐fullerene triad 138 was carried out in three steps. The process began with the synthesis of a meso‐phenyl BODIPY‐ferrocene dyad 34 [13]. The meso‐phenyl BODIPY‐ferrocene dyad 34 was then converted into a dioxyboron dipyrrin derivative 137 by treating it with dihydroxybenzaldehyde in the presence of AlCl₃ in dry DCM. Finally, the C₆₀ was attached by reacting the dioxyboron dipyrrin derivative 137 with fullerene and N‐methyl glycine in toluene using the Prato reaction [51]. PET studies, performed using femtosecond transient spectroscopy, demonstrated charge stabilization within the resulting triad 138 (Scheme 26).

SCHEME 26.

Synthesis of BODIPY‐ferrocene‐fullerene triad 138.

In Fc‐BODIPY‐C₆₀ triad 146 and [Fc]₂‐BODIPY‐C₆₀ tetrad 147, one or two ferrocene entities are linked to the β‐positions of the BODIPY core by an ethynyl bridge [47]. The β‐mono‐iodo BODIPY 139 or β‐bis‐iodo BODIPY 142 precursors were synthesized by the literature method in 66% and 90% yields, respectively (Scheme 27a) [4]. The desired β‐mono‐ethynylBODIPY‐ferrocene (Fc‐BODIPY) 142 and β‐bis‐ethynyl‐BODIPY‐ferrocene ([Fc]₂‐BODIPY) 143 were obtained efficiently in 80% and 76% yields, by reacting the precursors 139 and 142, respectively, with an excess of ethynylferrocene 19 under Sonogashira cross‐coupling reaction conditions (Scheme 27a) [29, 30]. BODIPY‐ferrocene azide derivatives 141 and 144 were then prepared using a one‐pot procedure [52], reaction of BODIPY‐ferrocene 140 and 143 with NBS and PPh₃ in DCM at 0°C for one hour resulted in the formation of a new compound bromoBODIPY intermediate. Then, the reaction of this intermediate bromo derivative with NaN₃ (25% in H₂O) and two drops of Aliquat 336 at 80°C afforded the desired azido BODIPY 141 in 50% yield and [Fc]₂‐BODIPY azide conjugate 144 in 47% yield. Finally, the azido‐Fc‐BODIPY 141 and [Fc]₂‐BODIPY azide conjugate 144 were reacted with methanofullerene platform 145, bearing on one side an alkyne and on the other a protected alkyne, under CuAAC conditions in the presence of CuBr and DIPEA in DCM_, yielding the target Fc‐BODIPY‐C₆₀ triad 146 in 91% [Fc]₂‐BODIPY‐C₆₀ tetrad 147 in 77% yield respectively (Scheme 27b). Due to the extended π‐conjugation and the presence of an ICT band from ferrocene to BODIPY, all these conjugates display a broad absorption in the visible region, which is bathochromically shifted when two ferrocenes are appended to the BODIPY core. Ultrafast multistep electron transfer leading to charge stabilization were demonstrated in the Fc‐BODIPY‐C₆₀ triad 146 and [Fc]₂‐BODIPY‐C₆₀ tetrad 147 by femtosecond transient absorption studies.

SCHEME 27.

(a) Synthetic strategies for the formation of BODIPY‐ferrocene azide derivatives 141 and 144. (b) Synthesis of BODIPY‐ferrocene‐fullerene triads 146 and tetrad 147.

A series of covalent BODIPY‐ferrocene‐fullerene triads 149a–149e with the ferrocene groups conjugated to the BODIPY π‐system and the fullerene acceptor linked at the boron hub via a common catecholpyrrolidine bridge were prepared [16]. BODIPY‐ferrocene‐fullerene tetrad 149a,d and triads 149b‐c,e were prepared using the authors' previously reported BODIPY‐ferrocene dyads 148a–148e, starting the synthesis as outlined in Scheme 28a [35]. The choice of a catecholpyrrolidine‐bridged fullerene as the terminal electron acceptor was based primarily on three factors. First, this architecture has been reported to be effective at promoting the desired excited‐state electron transfer [35]. Second, by interrupting conjugation, the bridge is expected to limit electronic coupling between the BODIPY‐ferrocene donor and the fullerene acceptor, thereby potentially extending the lifetime of the targeted charge‐separated state. Third, the catecholpyrrolidine‐bridged fullerene can be readily synthesized. Tetrad 149a,d and triads 149b‐c,e were prepared in two steps, first, a catecholaldehyde fragment was introduced by ligand exchange between [Fc]₂‐BODIPY 69, mono‐BODIPY‐ferrocene 70, 71, and 74 with the catechol, respectively [53]. Subsequently, fullerene was covalently bonded to the [Fc]₂‐BODIPY 69, mono‐BODIPY‐ferrocene 70, 71, and 74 by Prato reaction [54]. To investigate the influence of the fullerene‐to‐BODIPY distance and orientation on the PET, two isomeric tetrad [Fc]₂‐BODIPY‐C₆₀ 149a and 149d were prepared, which differed by the catechol group linkage (2,3‐ and 3,4‐) to fullerene acceptor, respectively (Scheme 28a). Reference BODIPY‐fullerene dyad was prepared via BODIPY 148f using BODIPY 68 with the catechol as illustrated in Scheme 28b.

SCHEME 28.

(a) Synthesis of BODIPY‐ferrocene‐fullerene tetrad 149a,d and triads 149b‐c,e. (b) Synthesis of reference BODIPY‐fullerene dyad 149f.

All compounds were characterized by 1D and 2D NMR, UV–vis, steady‐state fluorescence spectroscopy, high‐resolution mass spectrometry and for one of the derivatives, x‐ray crystallography. Redox processes of the new compounds were investigated using CV, differential pulse voltammetry (DPV), and spectroelectrochemistry. DFT calculations indicated that the HOMO states in all BODIPY‐ferrocene‐fullerene tetrad 149a,d and triads 149b‐c,e were delocalized between ferrocene and BODIPY π‐system. However, LUMO was always fullerene‐centered, and the catechol‐centered occupied orbital was close in energy to the HOMO. Time‐dependent density functional theory (TDDFT) calculations were indicative of the low‐energy, low‐intensity charge‐transfer bands originating from the BODIPY‐Ferrocene core to fullerene excitation, which explained the similarity of the UV–vis spectra of the BODIPY‐Ferrocene dyads 148a‐e and BODIPY‐ferrocene‐fullerene triads. Photophysical properties of the BODIPY‐ferrocene‐fullerene tetrad 149a,d and triads 149b‐c,e as well as reference BODIPY‐Fullerene dyad 149f were investigated by pump‐probe spectroscopy in the UV–vis and NIR spectral regions following selective excitation of the BODIPY‐based antenna. Initial charge transfer from the ferrocene to the BODIPY core was shown to outcompete sub‐100 fs deactivation of the excited state mediated by the catechol bridge. However, no subsequent electron transfer to the fullerene acceptor was observed. The initial charge‐separated state relaxes via recombination with a time constant of 150–380 ps.

11. Miscellaneous

11.1. BODIPY‐Porphyrin‐Ferrocene Antenna System

In 2014, Lim and coworkers synthesized and characterized a novel photosynthetic‐antenna‐reaction‐center model compound 153 [55]. This complex system consists of: A BODIPY as the energy‐harvesting antenna, zinc porphyrin (ZnP) as the primary electron donor, ferrocene as a hole‐shifting agent and phenylimidazole‐functionalized fulleropyrrolidine (C₆₀Im) as an electron acceptor. The synthesis of the core Fc‐ZnP‐BODIPY triad 151 involved several steps: 4‐ferrocenylaniline (Fc‐NH₂) 10, the amino‐functionalized BODIPY 60, and dicarboxylic‐acid‐functionalized free‐base porphyrin (HOOC‐H₂P‐COOH) 150 were prepared according to slightly modified literature methods (Scheme 29) [56]. The dicarboxylic acid group of porphyrin 150 was treated with SOCl₂ to form the porphyrin acid chloride intermediate. Later, this intermediate was reacted with equimolar mixtures of Fc‐NH₂ 10 and NH₂‐BODIPY 60 in the presence of pyridine in toluene to yield Fc‐H₂P‐BODIPY triad, followed by purification. Lastly, the resulting Fc‐H₂P‐BODIPY was metalated using zinc acetate to obtain the final Fc‐ZnP‐BODIPY triad 151. The energy‐harvesting antenna 153 was prepared by reacting the supramolecular assembly of the Fc‐ZnP‐BODIPY triad 151 with C₆₀Im 152 through metal‐ligand axial coordination. Spectral changes during the titration of C₆₀Im 152 to a solution of the Fc‐ZnP‐BODIPY triad 151 in dichlorobenzene (DCB) were studied. The observed spectral changes were consistent with ZnP binding to nitrogenous bases [57]. Specifically, red‐shifted Soret and visible bands of ZnP were observed; however, there were no changes in the peak maxima of BODIPY, suggesting a lack of interactions between BODIPY and the added C₆₀Im in solution. An isosbestic point at 419 nm was also observed, indicating the existence of an equilibrium process in solution. Photophysical studies, including optical absorption and emission spectroscopy, computational analysis, and cyclic voltammetry, helped to establish the role of each component in the multistep photochemical reactions. Selective excitation of the BODIPY antenna led to efficient singlet energy transfer to the ZnP moiety. Ultrafast electron transfer from the excited ZnP (¹ZnP*) or the fullerene (¹C₆₀*) formed the Fc‐(C₆₀ ⁻Im:ZnP⁺)‐BODIPY radical ion pair, which was observed via femtosecond transient absorption studies. Subsequent hole migration to the ferrocene resulted in the long‐lived Fc⁺‐(C₆₀ ⁻Im:ZnP)‐ radical ion pair, which persisted for 7–15 µs. The study successfully demonstrated the utility of this “antenna‐reaction‐center” model system for generating a long‐lived charge‐separated state, thereby improving the utilization of light energy (Scheme 29).

SCHEME 29.

Synthesis of Fc‐ZnP‐BODIPY 151 and photosynthetic‐antenna‐reaction‐center 153.

11.2. BODIPY‐Ferrocene‐Pyrene Conjugate

Studies of BODIPY‐ferrocene‐pyrene triad 157, having a conjugated pyrene fragment appended to the α‐position of the BODIPY‐ferrocene dyad 155, were demonstrated by Zatsikha and Nemykin [58]. BODIPY‐Pyrene dyad 155 and triad 156 were prepared using the Knoevenagel condensation reaction approach. Reaction between starting BODIPY 72 and 1‐pyrenecarboxaldehyde 154 leads to the formation of mono‐ and dipyrene‐containing BODIPYs 155 and triad 156, respectively, which can be easily separated using standard purification techniques. The further reaction between mono‐pyrene‐containing BODIPY 155 and ferrocenecarboxaldehyde 3 leads to the formation of ferrocene‐containing pyrene‐BODIPY 157 (Scheme 30). The BODIPY‐ferrocene‐pyrene triad 157 has both pyrene and an additional electron‐donating ferrocene group to facilitate PET to the photoexcited BODIPY chromophore. The redox properties of BODIPY‐ferrocene‐pyrene dyad 155 and triad 157 were studied by CV, DPV and spectroelectrochemical approaches. Formation of weakly bonded non‐covalent complexes between the new BODIPY‐ferrocene‐pyrene triad 157 and nano carbon materials (C₆₀, C₇₀, single‐walled carbon nano tube (SWCNT), and graphene) was studied by UV–vis, steady‐state fluorescent, and time‐resolved transient absorption spectroscopy. UV–vis and fluorescence spectroscopy indicated much stronger and more selective interactions between the BODIPY‐ferrocene‐pyrene triad 157 and (6,5)‐SWCNT, as well as graphene, compared with those of the C₆₀ and C₇₀ fullerenes. Transient absorption spectroscopy showed that there were no significant changes in the excited‐state lifetime [21] or photoinduced charge transfer between pyrene‐BODIPYs and C₆₀ or C₇₀ fullerenes. This was observed when the pyrene‐BODIPY chromophores were excited into their lowest‐energy singlet excited state. DFT and TDDFT calculations showed that the pyrene fragments are fully conjugated into the π‐system of the BODIPY core, which correlates well with the experimental data.

SCHEME 30.

Synthesis of pyrene‐BODIPY dyad 155 and BODIPY‐ferrocene‐pyrene triad 157.

11.3. BODIPY With Ferrocene Substituent at Boron Atom

Bis(ferrocenyl)‐functionalized BODIPY compounds 160 and 162 featuring direct ferrocene‐boron bonds were obtained via a “prefunctionalization strategy” [59]. Authors reported that compound 160 was prepared using the “prefunctionalization” method, starting from diferrocenylboron bromide (Fc₂BBr) 158. Fc₂BBr was prepared according to a procedure developed by Wagner et al., as shown in Scheme 31 [60]. Complexation of Fc₂BBr 158 with dipyrromethene 48 in the presence of lithium diisopropylamide (LDA) afforded the desired product 160 as dark‐green crystals after purification by column chromatography. Compound 162 containing alkyne bridges was prepared to examine the impact of the linker on the photophysical properties. The alkynyl Grignard reagent 161 was generated in situ by reacting ethynylferrocene 19 with isopropylmagnesium bromide. Subsequently, the resulting Grignard mixture was used for nucleophilic substitution of the BODIPY 48 to generate the target compound 162 (Scheme 31). UV–vis absorption, electrochemical, and transient absorption experiments were performed on compounds 160 and 162 to examine the impact of ferrocenyl substitution on the electronic properties. Authors showed that ferrocene units were found to have a negligible impact on the absorption spectrum of the BODIPY unit but significantly altered its excited‐state dynamics.

SCHEME 31.

BODIPY‐ferrocene triad containing direct bridge 160 and alkyne bridge 162.

In all BODIPY‐ferrocene conjugates studied by electrochemical and, in some cases, spectroelectrochemical or chemical oxidation methods, the first oxidation process was attributed to the oxidation of ferrocene fragment (Table 1). Usually, additional irreversible oxidation and reversible reduction processes centered at the BODIPY core are also observed in electrochemical experiments on these compounds. Assignment of the first oxidation process was not only confirmed based on the similarity of the oxidation potential of unsubstituted ferrocene, but also, in some cases, based on spectroelectrochemical and chemical oxidation data.

12. Challenges and Future Opportunities

Despite thorough and explicit work in the field of BODIPY‐ferrocene adducts, several challenges remain, like oxidative instability of ferrocene under prolonged exposure to light or aerobic conditions, which limit stability [61] and application in practical devices, and poor aqueous solubility/bioavailability [62], hindering biomedical translation. Synthetic scalability remains a challenge due to multi‐step reactions prone to side products. In the case of complex triads/tetrads, there is still a lack of control over energy/electron transfer, limiting their application to steady‐state spectroscopy. However, future opportunities seem to be in the areas of developing sterically shielded or encapsulated BODIPY‐ferrocene hybrids, which could enhance stability for NIR optoelectronics; water‐soluble variants with targeting ligands (e.g., biotin‐ferrocene‐BODIPY) hold promise for theranostics; and multidimensional assemblies (e.g., BODIPY‐ferrocene polymers or MOFs) may enable ultrafast switching for quantum technologies. In essence, while we have glimpsed a fraction of the BODIPY‐ferrocene universe, its vast potential awaits innovative exploration.

13. Conclusion

Ferrocene has attracted significant attention since its discovery in 1951, owing to its remarkable reversible electrochemical properties and exceptional stability, making it an ideal building block for the development of functional materials. BODIPY generally absorb at higher energy with the singlet state energy level. The installation of the redox‐active ferrocene unit into the BODIPY framework results in D–A hybrid systems with interesting electrical and photophysical properties. As discussed in this review, BODIPY‐ferrocene conjugates have been prepared using a variety of synthetic strategies, including cross‐coupling reactions, condensation methods, and click chemistry, resulting in a wide range of architectures, for example dyads, triads, and tetrad systems with additional functional units (ferrocene, BODIPY, merocyanine, porphyrin, fullerene, and biotin). Ferrocene is highly useful in push–pull chromophores due to its strong electron‐donating ability, enabling efficient ICT and tunable optical properties. This facilitates the design of dyes with absorption in the visible to NIR/IR regions, making them suitable for applications in telecommunication and defence. Such hybrids have also shown potential in sensor fabrication, photovoltaics, and medical applications, including cancer diagnosis and therapy.

To summarize, the collective work described in this review indicates that “we know a small part of the world of BODIPY‐ferrocene conjugates but that we still have the rest of their universe to discover”. There is plenty of room to create novel dyads and triads, establishing structure‐property relationships, and finding new applications for them. Additionally, the development of simpler, scalable, and sustainable synthetic methodologies is necessary for practical applications. Future research should focus on exploring new architectures with advanced performance and integrating these systems into functional devices.

Overall, BODIPY‐ferrocene conjugates represent a versatile and evolving class of materials with considerable potential, offering exciting opportunities for further exploration in both fundamental and applied research.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.