BODIPY

The unique properties of BODIPYs arise in their photo-stability and high molar absorption coefficients. Unlike most other commonly available photocages, BODIPYs have their absorption range in the visible light spectrum. The exact wavelength can be fine-tuned with the derivatisation of the chromophore which can be of special interest for uses in chemical sensors or fluorescent organic devices ¹⁸. Meso-methyl BODIPYs in particular are used in particular as photocages as they are able to release active organic compounds upon irradiation with light of a suitable wavelength ¹³. Especially the high emission quantum yields of meso-methyl derived BODIPY structures and the possible usage for photo-release reactions are of interest. The high extinction coefficients and narrow absorption bands raise additional interest ^19,20.

In Figure 5 the photocleavage process in the meso-position of such a BODIPY compound and the release of the active substrate can be seen.

Figure 5: Schematic drawing of the photo- release process of BODIPY and an associated substrate.

Further advantages of BODIPY compounds compared to many other photocages are their biological compatibility as well as their sterically compact structure ²¹. Because BODIPYs show a low sensitivity towards pH changes and are stable under physiological conditions ²², applications in the field of tissue regeneration and drug delivery would be possible ^23,24.

7 Some basic BODIPY structures can be seen in Figure 6. The simplest structure on the top left is not reported in literature and predicted to be unstable, as the system is not sterically protected. In order to reduce the risk for any side reactions of BODIPY-compounds it is important that the framework is substituted ²⁵. The simplest synthesised structure on the top right is often viewed as reference to which other BODIPY-structures can be compared to.

Like stated above, the absorbance of the chromophore can be altered via chemical derivatisations. However, the differences in the fluorescence properties of these lower alkylated BODIPY compounds are rather small. Higher alkylated BODIPY-compounds like it can be seen in the lower right structure tend to have a bit higher absorption maxima (528 nm) compared to lower substituted analogous like in the upper right structure (507 nm) ²⁶.

Figure 6: Basic BODIPY-structures with different substituents, adapted from literature ²⁶.

8 Next to parameters like light intensity, wavelength and duration of irradiation, also structural aspects play a role, affecting the speed and efficiency of the photocleavage ²⁷. Depending on the exact structure of the BODIPY compound the absorption wavelengths can be modified and tailored towards specific needs, as already mentioned ^28,13. Not only is the type of substituents important but also its position in the system. Substituents in position 8 have a low impact on the photodynamic properties, whereas large electron-donating groups in position 2 and 6 can lead to a substantial red shift of the absorbance ²⁹. Especially the introduction of heavy atoms like halogens can not only increase the absorption wavelength but can also increase the photocleavage efficiency. This is due to an increased intersystem crossing (ISC) efficiency if the leaving group is liberated from the triplet excited state. The fluorescence quantum yields decrease with an increased molecular weight of the substituents in position 2 and 6 (I > Br > Cl > H), most likely due to increased ISC. It was found that the photocleavage efficiency can be increased proportionally to ISC quantum yields. In general, substituents which increase ISC and therefore lower the barrier for a release on the triplet state can improve the photocleavage efficiency drastically ¹³.

Furthermore, an increase of the conjugated system as through styryl- functionalised BODIPY-compounds can lead to absorption windows even over 700 nm which allows a deep tissue penetration ³. In Figure 7 an example for a 3,5-distyryl functionalised BODIPY structure can be seen.

Figure 7: Chemical structure of 3,5-distyryl functionalized BODIPY with absorption wavelengths around 700 nm ³.

9 Also, aryl-modified BODIPYs show absorption windows at the near IR spectrum.

The high rigidity of their π-system leads to high fluorescence quantum yields ³⁰. It has been reported that BODIPY-compounds with an alkylated boron centre have higher fluorescence quantum yields than a fluorinated boron centre. However, it is also dependant which kind of alkyl group is attached to the boron atom. It has been shown that via irradiation existing alkyl groups can be cleaved and substituted with fitting solvent molecules ³¹. In Figure 8 the cleavage of alkyl-groups and the introduction of a methoxy-functionality is depicted. It is described that the compound on the right has a higher fluorescence quantum yield than the compound on the left by the factor 6.

Figure 8: Light induced substitution reaction on the boron-centre of a BODIPY compound for modification of photochemical properties of the fluorophore with their corresponding fluorescence

quantum yields ³¹.

The peak absorption can not only be altered through the introduction of different ligands, the BODIPY backbone itself can be modified. By the introduction of a nitrogen in position 8, aza-BODIPYs can be produced which can have absorption areas which extend into the near- infrared ³². However, because the meso-position can no longer be alkylated the uses as photocages are limited. In Figure 9 a comparison between the BODIPY and the aza-BODIPY structure can be seen.

10 Figure 9: Comparison of the aza-BODIPY (left) and BODIPY structure (right).

Whereas BODIPYs are typically very well soluble in most organic solvents ³³, a challenge arises in their poor water solubility ³⁴. This can be generally improved through the introduction of ionisable groups on the fluorophore or by the incorporation of the BODIPY into the backbone of a hydrophilic polymer ³⁵. While many of these alterations can improve the solubility, the photodynamic properties of the compounds are changed as well which can make them unsuitable for their intended usage ³⁴. An advantage of the introduction of ionisable groups lies within their easy implementation and small size. It is however possible that these ionic functionalities undergo non-specific interactions with chemicals or other biomolecules. Non-ionic water soluble BODIPY compounds are therefore superior in avoiding such side reactions, however they often depend on long sidechains like poly(ethyleneglycol) to achieve a sufficient water solubility ³⁶.

Another method that is used in order to improve the water-solubility of BODIPY-compounds involves the introduction of sulfonate groups. However, with a conventional 2,6-sulfonation, the BODIPY structures can become unsuitable for photocleavage due to the strong electron-withdrawing effect of the substituent destabilizing the cleavage intermediate. To overcome this problem the sulfonate groups were positioned via an alkyl-residue at the 3 and 5 positions. The resulting compound, depicted in Figure 10, showed a better water-solubility and adjustable cell permeability depending on the degree of sulfonation. Possible uses may therefore arise as modulation agents for cell surface receptors ³⁷.

11 Figure 10: Chemical structure of a water-soluble BODIPY-compound ³⁷.

A factor that can hinder an effective photocleavage of BODIPYs is aggregation caused quenching (ACQ) ³⁸. It has been a long reported problem also with other light emitting compounds, especially in the near-infrared light spectrum ³⁹. This can lead to their dark and non-emitting appearance in high concentration or as a solid.

The small stokes-shift and the therefore high self-absorption of the emitted light can be seen as the main reason for this quenching effect ⁴⁰. In highly concentrated solutions or in solid state usage the emission could therefore be massively reduced ⁴¹. This has to be taken into account when incorporated into polymeric structures to avoid undesired quenching when integrated in close proximity.

BODIPY- compounds opened new ways in various application as, for example, in photodynamic therapy, which is seen as one of the most promising methods in the treatment of cancer ⁴². Photodynamic therapy involves a photosensitive substance like BODIPY, which is injected into specific part of the body. Upon irradiation singlet oxygen can be produced in a sequence of steps which can consequently damage the target tissue ⁴³. BODIPYs have also found its use in other cancer treatments.

It has been covalently bound to capsaicin. Capsaicin has not only found its treatment in inflammatory treatments but also shows promising results in anti-tumor activity. With the usage of this covalently bound CAP-BODIPY complex the efficiency in prostate cancer treatments could be increased ⁴⁴. The various fields of application show the importance of BODIPY and its derivatives ⁴⁵.

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