4,4′-Dicyano- versus 4,4′-Difluoro-BODIPYs in Chemoselective Postfunctionalization Reactions: Synthetic Advantages and Applications

The presence of F or CN substituents at boron in BODIPYs causes a dramatic effect on their reactivity, which allows their chemoselective postfunctionalization. Thus, whereas 1,3,5,7-tetramethyl B(CN)2-BODIPYs displayed enhanced reactivity in Knoevenagel condensations with aldehydes, the corresponding BF2-BODIPYs can experience selective aromatic electrophilic substitution (SEAr) reactions in the presence of the former. These (selective) reactions have been employed in the preparation of BODIPY dimers and tetramers, with balanced fluorescence and singlet oxygen formation, and all-BODIPY trimers and heptamers, with potential application as light-harvesting systems.

B ODIPY (4,4′-difluoro-4-bora-3a,4a-diaza-s-indacene) dyes, e.g., 1 (Figure 1), 1 have become one of the most appealing families of small-molecule organic fluorophores. 2ODIPY dyes have found wide application in a variety of fields of modern science from biology to material sciences, e.g., triplet photosensitizers, 3 photodynamic therapy, 4 photocatalysts, 5 labeling of biomolecules, 6 photocleavable protecting groups, 7 and light-harvesting systems. 8However, what makes them unique is arguably the ability to fine-tune their photophysical properties and their chemical stability, among others, by subtle postfunctional modifications. 9For instance, chemical modifications at boron result in improved quantum yields, stability, and solubility while preserving their photophysical properties. 10In this context, photophysical studies of 4,4′-dicyano-BODIPYs, e.g., 3 (Figure 1), 11 readily available from 4,4′-difluoro-BODIPYs, e.g., 1 and 2 (Figure 1), have shown that they display enhanced fluorescent quantum yields and photostability compared to those of the latter fluorophores. 12Nevertheless, recent investigations showed that 4,4′-dicyano-BODIPYs are significantly more resistant to trifluoroacetic acid than the corresponding difluoro-BODI-PYs. 13This enhanced chemical stability toward acid on dicyano-BODIPYs 6b,14 was attributed to a strengthening of the B−N bonds, owing to the higher aromaticity of the former.12b Along this line, and on the basis of our own experience with dicyano-BODIPYs, 12d,15 we anticipated that the dissimilarity mentioned above, along with the recognized different electronwithdrawing capacity of CN versus F substituents, 13a might translate into contrasting reactivities at specific positions of the dipyrromethene core between B(CN) 2 -and BF 2 -BODIPYs. 16n the work presented here, we have evaluated some of these reactivities (Figure 1), and we report that whereas 8-aryl-1,3,5,7-tetramethyl CN-BODIPYs [3 (Figure 1)] are more reactive than related F-BODIPYs [2 (Figure 1)] in Knoevenagel-type condensations, the corresponding S E Ar reactions are favored in F-BODIPYs versus CN-BODIPYs.We have also demonstrated how these reactivity differences can be incorporated into chemoselective synthetic protocols leading to differently functionalized BODIPY heterodimers, and all-BODIPY trimers and heptamers, with relevant photophysical properties.
3,5-Distyryl-boradiazaindacene derivatives are relevant BODIPY dyes 23 whose synthesis, by Knoevenagel condensation, can be facilitated by increasing the acidity of the methyl groups at C3 and C5. 24On the basis of previous studies, 13 which had shown that replacement of the fluorine atoms with cyano groups in BODIPYs decreases the charge at boron, we hypothesized that the acidity of the methyl groups at C3 and C5 would be enhanced on the latter, thereby accelerating Knoevenagel condensations in B(CN) 2 -BODIPYs compared to those in BF 2 -BODIPYs.Our initial results seemed to prove our hypothesis (Schemes S13 and S14).Thus, Knoevenagel condensation (PhCHO, piperidinium acetate, DMF) of a mixture of BODIPYs 2a and 3a yielded only mono-and distyryl derivatives arising exclusively from B(CN) 2 -BODIPY 3a, and leaving BF 2 -BODIPY 2a unreacted (Scheme S15).Along this line, Knoevenagel condensations of BODIPY heterodimer 8 with benzaldehyde or with formyl BODIPY 14a (Figure 4) yielded heterodimer 15 and all-BODIPY tetramer 16 in 80% and 54% yields, respectively (Figure 4).In the latter example, neither self-coupling of BODIPY 14a nor the formation of BODIPY oligomers arising from condensation at the BF 2 -BODIPY half of heterodimer 8 was observed.
To demonstrate the value of these transformations in the preparation of BODIPY-based structures with balanced fluorescence and singlet oxygen formation, 25 we synthesized di-iodinated derivatives 17 and 18 by chemoselective halogenation of compounds 15 and 16, respectively (Figure 4).
Furthermore, the chemoselective Knoevenagel condensation of aldehydes has been employed in the preparation of all-BODIPY heptads 21 and 24 for their study as light-harvesting systems.Accordingly, Knoevenagel condensation of 3b with formyl-BODIPY 14b produced trimer 19 in moderate yield.Replacement of the fluorine atoms in 19 with cyano groups produced all-B(CN) 2 -BODIPY trimer 20, which upon Knoevenagel condensation with 14b furnished all-BODIPY heptamer 21 [8% yield, 18% corrected yield based on   ).The long-wavelength band corresponds to the πextended 3,5-styryl-BODIPY (635−670 nm, red-shifted when 2,6-phenylacetylenes are grafted), acting as the energy acceptor and final emitter.The short-vis wavelength is due to the alkylated BODIPYs (500−520 nm, red-shifted upon its further 2,6-ethylation) acting as an energy donor.Finally, the UV band (350 nm) is a trademark of styryl-substituted BODIPYs.The intensity of each band depends on the number of chromophores appended (Figure 6).
In addition, the fluorescence profile and efficiency markedly depend on the group replacing boron, type of spacer, and linkage positions.Trimers (19, 20, 22, and 23) emit efficiently [≤68% (Table 1)] featuring a single long-wavelength band [650−700 nm (Figure 6)], corresponding to the π-extended styryl-BODIPY, as result of an efficient (>98%) intramolecular excitation energy transfer (EET).The fluorescence of these trimers notably increases upon replacement of fluorine at the boron position with cyano moieties [19 vs 20 (Table 1)].However, an increase in solvent polarity induces an extremely weak emission.The linkage of donor and acceptor units through 3,5-styryl groups switches on photoinduced electron transfer (PET). 26The replacement of boron with a cyano group softens this PET-induced emission quenching, increasing the fluorescence response up to 1 order of magnitude in polar media [from 1% in 19 to 24% in 20 (Table S1)].The corresponding heptamers 21 and 24 show an intense panchromatic absorption (Figure 6), but an almost negligible emission even in low-polarity media (Table 1).Note that up to six donor−acceptor connections through 3,5-styryl units are established, further enhancing the PET-exerted quenching of the emission.The use of B(CN) 2 -BODIPY building blocks cannot counteract this quenching (Table S2).
The urea-bridged multichromophores feature similar photophysical behavior.Heterodimer 15 displays a notable red fluorescence (54% efficiency at 645 nm), moderately decreasing in polar media [to 26% (Table S3)] owing to the urea-induced through-space PET. 18The corresponding tetramer 16, in which up to three dissimilar BODIPYs are combined via a urea bridge and at-styryl linkage, renders broadband absorption featuring up to four bands (Figure 6).Unfortunately, the fluorescence efficiency is very low [<2% (Table 1)], owing to the synergy of both available PET pathways (through-space from the urea bridge and between BODIPYs).
The laser action of these multichromophores is guided by the photophysical behavior (Table 1).The highly fluorescent dimers and trimers render red-edge laser emission in the range   ), and laser (λ la ) wavelengths, molar absorption coefficients (log ε max ), fluorescence quantum yields (ϕ), and laser efficiencies.
of 690−735 nm with efficiencies ranging from 15% (19) to 50% (20).Additionally, they display a high photostability under laser pump conditions, especially as the number of peripherical BODIPYs All maintain their initial emission without a sign of photodegradation after 100 000 pump pulses.
The iodination of the urea-bridged multichromophores endows them with the ability to photosensitize singlet oxygen ( 1 O 2 ).Indeed, dimer 9, in which the iodinated BODIPY acts as an energy acceptor, exhibits a low fluorescence efficiency [<3% (Table S3)], owing to the heavy-atom-induced intersystem crossing (ISC), but efficient 1 O 2 generation (89%).The iodination of the donor BODIPY enables a balanced response.Thus, iodinated dimer 17 exhibits a notable red fluorescence [45% at 655 nm (Table S3)] while maintaining efficient 1 O generation (34%).The corresponding tetramer 18 also enables 1 O 2 generation, although the aforementioned PET reduces its fluorescence emission to merely 8% (Table S4).The phosphorescent emission (Figures S4 and S5) from dimer 9 features a single broad band at 750 nm, with a shoulder at 820 nm.However, multichromophoric dyes and 18 exhibit an additional long-lived emission at 1000−1200 nm (Figure S4).Theoretical calculations suggest that the lowest triplet state of styryl-BODIPY in dimer 17 is located 0.45 eV below that of iodinated dimer 9 (Figure S6), in good agreement with the recorded shift in the delayed spectra.Thus, upon excitation at the iodinated donor, a fraction of photons can populate the singlet state of the acceptor via EET and yield red fluorescence, but another fraction reaches the donor triplet state via ISC and, from here, the acceptor triplet state via triplet−triplet energy transfer. 27nce the dual fluorescence and 1 O 2 generation had been assessed using iodinated BODIPY as an energy donor (i.e., 17), the related dimer 25 was synthesized (Scheme S2).It differs from 17 in the nature of the linking bridge (amino vs urea).The overall photophysical signatures of 25 are similar to those recorded from 17, with a slightly lower fluorescence efficiency (34% in chloroform) but a fairly higher level of singlet oxygen generation (36%) (Table S3 and Figure S7).Therefore, the ISC population is driven almost exclusively by the heavy-atom effect, being that the contribution of a PETmediated mechanism almost vanished (Figure 7).
In summary, we have shown that replacing the fluorine atoms with CN groups at boron in BODIPYs causes remarkable changes in reactivity on their dipyrromethene core.To highlight the relevance and potential applications of these findings, we selected several well-known synthetic transformations in BODIPYs.Thus, whereas the reactivity of 3,5-dimethyl B(CN) 2 -BODIPYs is higher than that of the corresponding BF 2 -BODIPYs in Knoevenagel condensations, the latter display higher reactivity toward electrophilic reagents.This knowledge might prove of interest when planning efficient postfunctionalization reactions on BODIPYs.For instance, di-iodinated B(CN) 2 -BODIPYs, which cannot be obtained by direct iodination, are readily synthesized by the halogenation of BF 2 -BODIPYs followed by F → CN exchange at boron. 17Some synthetic applications based on these principles have also been described.The enhanced reactivity of B(CN) 2 -BODIPYs versus BF 2 -BODIPYs in Knoevenagel condensations has been used in an iterative protocol, employing formyl-BF 2 -BODIPYs and B(CN) 2 -BODIPYs as the coupling partners, which ultimately led to all-BODIPY heptamers, featuring panchromatic absorption and effective red−near-infrared fluorescent and laser emission over a broadband excitation window.Conversely, the preferred iodination of BF 2 -BODIPYs over B(CN) 2 -BODIPYs has allowed the efficient preparation of a BODIPY heterodimer with balanced fluorescence emission and singlet oxygen formation.These molecular assemblies show promise as lasers, light harvesters for sensitizing, and photosensitizers for theragnosis.