Fluorinated BODIPY Dyes | Encyclopedia MDPI

Fluorinated BODIPY Dyes: Comparison

Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Stefanie Casa.

The synthesis of fluorine-containing small molecules has had numerous benefits of improving the quality and efficiency of many applications of these compounds. Compounds such as derivatives of boron-dipyrromethene (BODIPY) typically demonstrate signal wavelengths around 500 nm and 600 nm; however, it is more favorable to see these signals closer to 700 nm to improve fluorophore applications. For this reason, recent studies described further in the text demonstrate the applications of adding fluorine-based substituents and phenyl rings to the chemical designs, thus redshifting absorption and fluorescence wavelengths.

fluorine chemistry
optical fluorophores
PET imaging
PDT
contrast agents

1. Fluorinated BODIPY Dyes

Martinez Espinoza et al. studied the synthesis and effects of branched fluorinated chains off a BODIPY scaffold [21]. The synthetic design focused on the fluorinated chain placement in two different positions. One position was associated with an alkoxy group of the meso position of the dye, as seen in compound

Martinez Espinoza et al. studied the synthesis and effects of branched fluorinated chains off a BODIPY scaffold ^[1]. The synthetic design focused on the fluorinated chain placement in two different positions. One position was associated with an alkoxy group of the meso position of the dye, as seen in compound

(

Scheme 1

). The scheme begins with a substitution reaction between 4-hydroxybenzaldehyde reacting with fluorinated mesylate (Rf-OMs) under basic conditions to generate aldehyde

. Using this intermediate, a fluorinated BODIPY

, is formed in three steps typical of BODIPY scaffold formation. The following step is iodination to add iodine atoms to the BODIPY core; this modification is described to promote singlet oxygen generation in the final compound. The step after iodination adds two equivalents of

-tolualdehyde to the scaffold through Knoevenagel condensation to extend the conjugation of the final compound

with a yield of 49%.

Scheme 1. BODIPY with multi-branched fluorinated chains on meso phenyl [21].

BODIPY with multi-branched fluorinated chains on meso phenyl ^[1].

The other placement was a substitution of fluorine atoms at the boron center with alkoxy groups containing the fluorinated chain as seen in compounds

and

(

Figure 3) [21]. In these dyes, an iodination step occurs to add iodine atoms to the BODIPY core to promote singlet oxygen generation. Both compounds contain a substitution to gain the fluorinated branches; however, compound

) ^[1]. In these dyes, an iodination step occurs to add iodine atoms to the BODIPY core to promote singlet oxygen generation. Both compounds contain a substitution to gain the fluorinated branches; however, compound

undergoes Knoevenagel condensation to extend conjugation before substituting the fluorine atoms. The structural differences in compounds

and

compared to compounds

and

are important to consider when determining the bathochromic shift caused by the substitution of the fluorinated chains because it is important to understand the impact of the fluorinated chains with and without the extended conjugation.

Figure 3. BODIPY with multi-branched fluorinated chains attached to boron center [21].

BODIPY with multi-branched fluorinated chains attached to boron center ^[1].

Another example of fluorine substitution on the boron center is viewed in the synthesis conducted by Duran-Sampedro et al. (Equation (1)). Trifluoroacetoxy groups replace both fluorine atoms [22]. The synthesis was accomplished to demonstrate the enhanced fluorescent effect of trifluoroacetoxy compared to a BODIPY with a standard core. This substitution method requires reagent TMSOCOCF

Another example of fluorine substitution on the boron center is viewed in the synthesis conducted by Duran-Sampedro et al. (Equation (1)). Trifluoroacetoxy groups replace both fluorine atoms ^[2]. The synthesis was accomplished to demonstrate the enhanced fluorescent effect of trifluoroacetoxy compared to a BODIPY with a standard core. This substitution method requires reagent TMSOCOCF

₃

, which is synthesized using trifluoroacetic acid and TMSCl in 1,2-dichloroethane, to react with individual compounds

–

. The reaction affords solid compounds

–

(yields 22–37%) with fluorine demonstrating halogenic effects in the boron center of the BODIPY.

In the next example, the aza-BODIPY

was synthesized as a trimodal contrast agent designed for fluorescence imaging, photoacoustic imaging, and

¹⁹F MRI [35]. Of the listed modalities, the BODIPY core demonstrates extended conjugation for enhancing fluorescence and photoacoustic imaging, and the trifluoromethyl groups on the aromatic ring are designed for

F MRI ^[3]. Of the listed modalities, the BODIPY core demonstrates extended conjugation for enhancing fluorescence and photoacoustic imaging, and the trifluoromethyl groups on the aromatic ring are designed for

¹⁹

F MRI functionality. In

Scheme 2

, the synthesis of contrast agent

begins with the ring closure of the BODIPY using compound

with ammonium acetate in ethanol under microwave conditions; the second step completes the closure using a boron-source to yield BODIPY

. A nucleophilic substitution reaction occurs between compound

and 3-bromo-propyne to form compound

. Through click chemistry, alkyne

forms a five-membered triazole ring with azide

to yield final compound

in a good yield of 41%.

Scheme 2.

Synthesis of fluorinated trimodal BODIPY

16 [35].

^[3].

Scheme 3 illustrates the synthesis of fluorinated BODIPY synthesized using a gold catalyst for the cycloisomerization of the fluorine-containing pyrrole precursor [36]. In previous literature, research groups have been studying the use of aromatic groups to extend conjugation of BODIPY dyes [17]. In this study, they synthesize pyrrole rings with aromatic rings containing trifluoromethyl group(s). The first reaction shown in

illustrates the synthesis of fluorinated BODIPY synthesized using a gold catalyst for the cycloisomerization of the fluorine-containing pyrrole precursor ^[4]. In previous literature, research groups have been studying the use of aromatic groups to extend conjugation of BODIPY dyes ^[5]. In this study, they synthesize pyrrole rings with aromatic rings containing trifluoromethyl group(s). The first reaction shown in

Scheme 3

is the two steps done on compound

to form the pyrrole

. The first step demonstrates the use of the gold catalyst in ionic liquid, and the second step shows the basic conditions to finalize the ring closure. After generating the relevant pyrrole, the BODIPY scaffold is synthesized using the pentafluorobenzaldehyde and pyrrole

with BODIPY reagents: chloroanile, BF

₃

·Et

₂

O, and DIPEA; this reaction generates product

in good yield 68–70%.

Scheme 3. Fluorinated BODIPY synthesized via gold catalyst [36].

Fluorinated BODIPY synthesized via gold catalyst ^[4].

In an effort to design a BODIPY dye with higher photostability, Hecht et al. synthesized a series of fluorinated BODIPY dyes and fluorinated BODIPY dyes with extended conjugation of the alpha-3 and alpha-5 positions [37]. As shown in

Scheme 4

, compound

was synthesized using the general BODIPY procedure to obtain compound

, followed by a Knoevenagel condensation using a fluorine-containing benzaldehyde. The Knoevenagel condensation is achieved utilizing a benzaldehyde derivative and a piperidinium acetate catalyst. This conjugation extension is used to shift BODIPY absorption values to higher wavelengths. The yield reported for the synthesis of dye

is 21%.

Scheme 4. Synthesis of BODIPY containing fluorinated aryl groups [37].

Synthesis of BODIPY containing fluorinated aryl groups ^[6].

Lastly, in

Figure 4

, the chemical structures of BODIPY compounds

and

are displayed. These compounds are relevant in recent literature for their biological applications. The design for dye

is similar to the rationale of compounds

–

5, with multi-branched fluorinated chains being the focus of the molecule [38]. The synthesis of dye

, with multi-branched fluorinated chains being the focus of the molecule ^[7]. The synthesis of dye

mostly addresses the fluorine exchange to generate the

¹⁸F-labeled BODIPY to introduce the PET modality to the scaffold for brain imaging [39].

F-labeled BODIPY to introduce the PET modality to the scaffold for brain imaging ^[8].

Figure 4.

Fluorinated BODIPYs used in

¹⁸FMRI and PET imaging modalities [38,39].

FMRI and PET imaging modalities ^[7][8].

3. Optical Properties of Fluorinated BODIPY

2. Optical Properties of Fluorinated BODIPY

BODIPY compounds typically demonstrate absorption spectra with a peak around 510 nm, typically more intense and relevant as a visible/NIR contrast agent. Newer dyes in literature have aryl groups in different positions of the BODIPY dye to afford shifts in wavelength that will improve in vivo applications. The most common is having a phenyl group at the meso position. Studies were conducted to view the effect fluorine atoms have on BODIPY when fluorine is observed in the meso phenyl at different placements [23]. These studies have indicated increasing absorbance values associated with increasing fluorine atoms in the molecule. They have also noted shifts in absorbance wavelength due to the position of the fluorine atoms in proximity to the BODIPY core. The absorption shift and increasing quantum yields are typically observed in compounds with halogens; however, the halogen’s position will affect the degree to which the increase is experienced.

BODIPY compounds typically demonstrate absorption spectra with a peak around 510 nm, typically more intense and relevant as a visible/NIR contrast agent. Newer dyes in literature have aryl groups in different positions of the BODIPY dye to afford shifts in wavelength that will improve in vivo applications. The most common is having a phenyl group at the meso position. Studies were conducted to view the effect fluorine atoms have on BODIPY when fluorine is observed in the meso phenyl at different placements ^[9]. These studies have indicated increasing absorbance values associated with increasing fluorine atoms in the molecule. They have also noted shifts in absorbance wavelength due to the position of the fluorine atoms in proximity to the BODIPY core. The absorption shift and increasing quantum yields are typically observed in compounds with halogens; however, the halogen’s position will affect the degree to which the increase is experienced.

Table 1

indicates the optical properties of BODIPY fluorophores shown in

and

and

, and Equation (1) with fluorine-containing functional groups/atoms at differing positions.

Table 1.

Optical properties of selected fluorine containing BODIPY dyes.

Dye	λ_Abs (nm)	λ_Em (nm)	ε (M⁻¹ cm⁻¹)	Stokes Shift (nm)	Φ_F	Solvent	Applications
2	531	550	103,000	21	0.05	THF	¹⁹F MRI
3	645	657	99,000	12	0.04	THF	¹⁹F MRI
4	531	551	138,000	20	0.04	THF	¹⁹F MRI
5	640	653	104,000	13	0.27	THF	¹⁹F MRI
9	502	509	102,000	7	0.95	Cyclohexane	Optical **
10	525	541	78,000	16	0.94	Cyclohexane	Optical **
11	532	571	54,000	39	0.76	Cyclohexane	Optical **
16	735	780	59,815	45	0.42	DMSO	¹⁹F MRI/NIR/PA
21	556	587	46,600	31	0.91	Acetonitrile	Optical **
22	550	587	58,100	37	0.94	Acetonitrile	Optical **
24	528	541	56,500	13	0.72	Acetonitrile	NIR *
25	637	650	70,500	13	0.80	Acetonitrile	NIR *
26	501	513	---	12	---	DCM	¹⁹F MRI
27	580	590	---	10	---	MeOH	PET

* NIR used for fluorescence imaging compounds; ** Optical used for compounds used for fluorescence studies in visible range.

Substitutions of fluorine on the boron of the BODIPY for trifluoroacetoxy causes a shift in peak absorbance wavelength [22]. Compared to the compounds created from the substitution of fluorine for acetoxy groups, compounds 9–11 demonstrate slightly blueshifted absorbance values, 502–532 nm; however, it demonstrates redshifted optical values compared to precursors 6–8 detailed in the literature. Quantum yield of compounds 9–11 does increase from the presence of fluorine in the trifluoroacetoxy groups compared to both the commercially available BODIPY 6–8 and the nonfluorinated versions of these fluorophores.

In the example of the trimodal BODIPY, compound

1 demonstrate slightly blueshifted absorbance values, 502–532 nm; however, it demonstrates redshifted optical values compared to precursors 6–8 detailed in the literature. Quantum yield of compounds 9–11 does increase from the presence of fluorine in the trifluoroacetoxy groups compared to both the commercially available BODIPY 6–8 and the nonfluorinated versions of these fluorophores.

In the example of the trimodal BODIPY, compound 16 was synthesized [35]. As expected, the addition of the component containing the trifluoromethyl groups did not afford a bathochromic shift as seen in other compounds; however, this was not expected due to the proximity of the fluorine to the BODIPY core. A significant increase in molar absorptivity, 59,815 M

was synthesized ^[3]. As expected, the addition of the component containing the trifluoromethyl groups did not afford a bathochromic shift as seen in other compounds; however, this was not expected due to the proximity of the fluorine to the BODIPY core. A significant increase in molar absorptivity, 59,815 M

⁻¹

, and quantum yield 42% were notably observed, like other fluorine-containing compounds.

Compounds

and

are similar in structure to compound

. They contain a fluorinated phenyl group in the meso position, either pentafluorophenyl or trifluoromethyl groups on phenyl. When comparing compounds

and

to compound

, the fluorinated phenyl affords a 10–16 nm shift. Most of the newer compounds in literature utilize a combination of increasing the conjugation of the BODIPY and increasing the number of fluorine atoms in the molecule to increase molecule absorbance around 30–200 nm. This shift in the wavelength offers the potential to push the synthesis of BODIPY compounds into the NIR optical window to improve the properties of these molecules applied as contrast agents without making them too large or complex.

2. Applications of Fluorinated BODIPY

3. Applications of Fluorinated BODIPY

Literature explores the lipophilic effect that is caused by fluorine atom in BODIPY dyes [23]. The fluorinated version of the BODIPY compounds is comparable to the version of the structure with hydrogen in the place of fluorine due to the compound’s size while offering electron-withdrawing halogenic effects to small molecules. This difference allows research to be done to compare hydrogen and fluorine atoms to explore the impact of fluorine atoms on BODIPY based on the quantity and position of atoms. Some of the most important studies to occur are the observations of fluorine substitutions on the center boron and observing fluorine effects on aromatic carbons.

Literature explores the lipophilic effect that is caused by fluorine atom in BODIPY dyes ^[9]. The fluorinated version of the BODIPY compounds is comparable to the version of the structure with hydrogen in the place of fluorine due to the compound’s size while offering electron-withdrawing halogenic effects to small molecules. This difference allows research to be done to compare hydrogen and fluorine atoms to explore the impact of fluorine atoms on BODIPY based on the quantity and position of atoms. Some of the most important studies to occur are the observations of fluorine substitutions on the center boron and observing fluorine effects on aromatic carbons.

Many well-known BODIPY dyes have been utilized for medical imaging. BODIPY dyes can be used as fluorescent switches and sensitizers for metal/pH sensing and being designed for specific cell or biomolecule targeting [18]. Although BODIPY compounds are typically hydrophobic compounds, which is a disadvantage for them to be utilized for biological applications, the addition and placement of the fluorine atoms can help overcome hydrophobicity [17]. In the example of

Many well-known BODIPY dyes have been utilized for medical imaging. BODIPY dyes can be used as fluorescent switches and sensitizers for metal/pH sensing and being designed for specific cell or biomolecule targeting ^[10]. Although BODIPY compounds are typically hydrophobic compounds, which is a disadvantage for them to be utilized for biological applications, the addition and placement of the fluorine atoms can help overcome hydrophobicity ^[5]. In the example of

Figure 5

, dye

16 is used as a trimodal contrast agent because, in acidic conditions, the agent will exhibit fluorescent properties [35]. Fluorescence imaging alongside photoacoustic imaging (PAI) and

is used as a trimodal contrast agent because, in acidic conditions, the agent will exhibit fluorescent properties ^[3]. Fluorescence imaging alongside photoacoustic imaging (PAI) and

¹⁹

FMRI allow for the activity of the compounds to be enhanced for tumor imaging and analysis. The fluorescence imaging shows the dye localizing to the tumor, while

¹⁹

FMRI and PAI imaging show sharp signals for the tumor cells.

Figure 5.

Applications of fluorinated trimodal compound

, for in vivo imaging. Imaging of an A549 tumor in the mouse model. Before injection (control,

top

) and after injection (

bottom

) demonstrating the three imaging modalities: NIR fluorescence (

left

¹⁹

FMRI (

middle

), and photoacoustic imaging (PAI) (

The introduction of fluorine atoms in these molecules shows improvements in the specificity of signal in certain forms of imaging.

Figure 6

shows imaging comparing

¹⁹

F signal to

H signal in a mouse model injected with 100 mM of compound

26, and the intensity of the fluorine signal in one location is appreciable [38]. The signal shows relatively high intensity for the fluorophore pictured (left); this compound has a similar structure to BODIPY compounds

, and the intensity of the fluorine signal in one location is appreciable ^[7]. The signal shows relatively high intensity for the fluorophore pictured (left); this compound has a similar structure to BODIPY compounds

–

featuring the multi-branch fluorination (

Scheme 1

). This observation is important to consider since the

¹⁹

F signal is very bright and localized to one area of the abdominal cavity, making it worth further investigating multi-branched fluorinated chains on BODIPYs.

Figure 6.

Dual fluorescence and

¹⁹

F MRI, dye

(100 µL of 100 mM in DCM). Image under black-light excited at 365 nm of mouse post-mortem (

left

); grayscale image (

right

) demonstrating overlay of

H and

One of the most interesting uses of these fluorine-containing BODIPYs is its applications in Positron Emission Tomography (PET) imaging [39,40].

One of the most interesting uses of these fluorine-containing BODIPYs is its applications in Positron Emission Tomography (PET) imaging ^[8][11].

Figure 7

demonstrates imaging after injection of compound

27 into a mouse model. It is observed that strong signals are observed in the brain upon 2 min of injection and diminishes in the images after 30 min. Although this is a short amount of time for a dye, this is an impressive achievement as many groups are pursuing brain-targeting probes. Although other compounds possess the potential for this type of application, these BODIPYs with the active fluorine substituted onto the boron have shown some of the most reports for PET imaging data in the literature, making fluorine-exchange on the boron well-known in BODIPY synthesis [39]. This functionality continues to be a growing interest in BODIPY research with continued improvements in the solubility of these compounds and the penetration of the blood–brain barrier.

into a mouse model. It is observed that strong signals are observed in the brain upon 2 min of injection and diminishes in the images after 30 min. Although this is a short amount of time for a dye, this is an impressive achievement as many groups are pursuing brain-targeting probes. Although other compounds possess the potential for this type of application, these BODIPYs with the active fluorine substituted onto the boron have shown some of the most reports for PET imaging data in the literature, making fluorine-exchange on the boron well-known in BODIPY synthesis ^[8]. This functionality continues to be a growing interest in BODIPY research with continued improvements in the solubility of these compounds and the penetration of the blood–brain barrier.

Figure 7.

Radioactive fluorine exchange in BODIPY used for PET, compound

. (

) PET imaging and (

) optical imaging was done at two intervals: 2 min and 30 min (0.1 GBq/µmol). (

) indicate MicroPET/CT images at the same intervals with an additional image at 60 min; (

) sagittal view and (

Some literature recognizes the potential for fluorinated BODIPY compounds to be used in cell imaging due to their lipophilic character having the potential for cell membrane staining [36]. The literature addresses the tremendous potential fluorine atoms cause for fluorescence imaging through improvements in molar absorptivity, increased fluorescence efficiency, and increased lasing efficiency [22]. However, most of the literature emphasizes the improvements in optical properties above all else on the effects fluorine has on BODIPY.

Some literature recognizes the potential for fluorinated BODIPY compounds to be used in cell imaging due to their lipophilic character having the potential for cell membrane staining ^[4]. The literature addresses the tremendous potential fluorine atoms cause for fluorescence imaging through improvements in molar absorptivity, increased fluorescence efficiency, and increased lasing efficiency ^[2]. However, most of the literature emphasizes the improvements in optical properties above all else on the effects fluorine has on BODIPY.

References

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