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Review

Bicyclic 1,3a,6a-Triazapentalene Chromophores: Synthesis, Spectroscopy and Their Use as Fluorescent Sensors and Probes

by
Yingchun Wang
,
Tomas Opsomer
and
Wim Dehaen
*
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Heverlee, Belgium
*
Author to whom correspondence should be addressed.
Chemosensors 2021, 9(1), 16; https://doi.org/10.3390/chemosensors9010016
Submission received: 17 December 2020 / Revised: 8 January 2021 / Accepted: 12 January 2021 / Published: 15 January 2021
(This article belongs to the Special Issue Organic Fluorescent Materials as Chemical Sensors)
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Abstract

:
The 1,3a,6a-triazapentalene (TAP) is an aromatic heterocyclic fluorescent dye with interesting features such as its small size, large Stokes shift, solvatochromism, and emission wavelengths that are spread across the visible spectrum. TAPs have been synthesized via different synthetic strategies involving click−cyclization−aromatization domino reactions, gold-catalyzed cyclization of propargyl triazoles or triazolization of acetophenones. As a result, TAPs with diverse substitution patterns were obtained, showing varying fluorescence properties. Based on these properties, several TAPs have been selected and studied as fluorescent imaging probes in living cells and as sensors. This mini review provides an overview of the research on the bicyclic TAPs and does not comment on the literature about benzo or otherwise fused systems. The synthetic methodologies for the preparation of TAPs, the substituent effects on the fluorescence properties, and the behavior of the TAP core as an element of biological imaging probes and sensors are discussed.

Graphical Abstract

1. Introduction

Organic fluorophores have been widely applied in modern science and technology as biological labels and probes [1,2,3,4,5,6], fluorescent sensors [7,8,9,10,11], etc. Advances in these applications are often driven by the development of new fluorescent dyes, aiming to acquire the desired physicochemical and photophysical properties. Therefore, the design of novel organic dyes and studying synthetic pathways for their preparation are relevant research areas that have received ample attention in recent decades [12,13,14,15,16]. However, most organic fluorophores are relatively large and hydrophobic, limiting their use in aqueous systems. In this regard, the 1,3a,6a-triazapentalene (TAP) sparked considerable interest upon its introduction a decade ago as a novel 10π-electron fluorophore due to its small size [17,18]. Generally, 1,3a,6a-triazapentalenes can be categorized into two types: (1) (hetero)aryl-fused and (2) the non-fused, simply bicyclic parent TAPs (Figure 1).
The (hetero)aryl-fused TAPs were reported for the first time in 1965 [19], and published methods to synthesize fused TAPs involve the deoxygenation of 1-(o-nitro(hetero)aryl)pyrazoles and thermolysis or photolysis of 1-(o-azido(hetero)aryl)pyrazoles [18,19,20,21,22], among others [23,24]. In general, the fluorescence properties of these fused TAPs are much less described, and this is why we will not include them in this literature study. However, we should mention a recent (2020) synthetic method based on intramolecular N-N bond formation of pyrazole-substituted aminopyridines and aminodiazines in the presence of hypervalent iodine(III) leading to tricyclic TAP derivatives with fluorescent behavior, that was published by Suzenet et al. [25]. This is a very interesting new development in TAP chemistry.
The bicyclic TAPs, which are the subject of this mini review, have been prepared via different synthetic pathways. Hirobe et al. were the first to report the bicyclic (non-fused) triazapentalenes in 1978 [26]. However, during the decades that followed, this heterocyclic scaffold was somehow not further studied, until a reappearance was made in 2011 [17]. Namba et al. cleverly applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction for the synthesis of the parent TAPs, which resulted in a number of valuable studies published by this group throughout the past decade [27,28,29,30]. Furthermore, these findings also encouraged other researchers to study the TAP fluorophore and to develop alternative methods for their preparation [31,32].
In this mini review, we will cover the different synthetic methods toward bicyclic triazapentalenes, along with the photophysical data and applications of the respective dyes. Throughout the remaining part of this text, TAP will only refer to bicyclic, non-aryl-fused triazapentalenes.

2. Synthetic Methods and Spectroscopic Properties

2.1. Aminopyrazole-Mediated Syntheses

The bicyclic 1,3a,6a-triazapentalenes, firstly reported by the Hirobe group, were synthesized via two different reaction pathways (Scheme 1) [26]. One pathway involved the synthesis of 3-acetyl-2-methyl-TAP 4. Starting from the parent pyrazole 1 and hydroxylamine-O-sulfonic acid 2, 1-aminopyrazole 3 was prepared and further reacted with 3-chloropentane-2,4-dione at elevated temperatures. In the next step, the resulting TAP 4 could be deacetylated under acidic conditions to afford the colorless 2-methyl-TAP 5 in the 95% yield. In another pathway, the 2-phenyl-TAP derivative 8 was synthesized through the amination of phenacylpyrazole 7 with O-(mesitylenesulfonyl)hydroxylamine 6. Interestingly, the deacetylated TAP 5 appeared to be sensitive to air and distinctly less stable compared to the 3-acyl derivative 4. The 2-phenyl-TAP 8 was slightly more stable than its methyl analog 5. From this initial study, the authors already recognized the stabilizing effect of an electron withdrawing group on the TAP core.

2.2. CuAAC-Based Syntheses

Namba et al. envisioned the renowned copper-click reaction as a valuable tool for the preparation of TAPs [17]. Starting from terminal alkynes 9 and 1-azidopropane building blocks 10 containing leaving groups (LG) at positions 2 and 3, the azide-alkyne cycloaddition in the presence of catalytic Cu(I) provided 1,2,3-triazoles as intermediate substrates. Next, cyclization of the 1,2,3-triazoles easily occurred in the basic environment via the substitution of one leaving group and was followed by the elimination of the second leaving group, causing aromatization (Scheme 2). Normally, the substituents on the azidopropanes were trifluoromethanesulfonate (triflate) groups. By changing the substituents on the alkynes and introducing additional side groups on the azido substrates, 3-unsubstituted TAP derivatives with various functionalization patterns were obtained by means of this general reaction pathway.

2.2.1. The 2-Substituted 1,3a,6a-Triazapentalenes

Various 2-substituted TAPs 12 were synthesized by the Namba group starting from terminal alkynes 9 and 3-azido-propane-1,2-diyl bistriflate 10a (Scheme 3) [17,28]. The reactions were carried out with copper(I) iodide, bis[2–(N,N-dimethylamino)ethyl] ether (BDMAEE) ligand and triethylamine (TEA) base in tetrahydrofuran (THF). It was found that the presence of an electron withdrawing group at the C2 position led to better reaction yields. Whereas the reaction with 4-nitrophenylacetylene reached a 96% yield of TAP 12g, TAP 12d with a 4-methoxyphenyl substituent was only obtained with a yield of 56%. Intriguingly, the unsubstituted triazapentalene 12b was obtained for the first time by the direct desilylation of crude 2-trimethylsilyl-TAP 12a. However, TAPs lacking an aryl substituent and 4-methoxyphenyl-TAP 12d gradually decomposed under UV irradiation. Therefore, it was confirmed that an electron poor aryl group is needed to stabilize the TAP core.
The fluorescent properties of TAPs were investigated by Namba et al. already in this first report and in subsequent articles. As indicated in Table 1, it was clear that the emission maxima of 2-substituted TAP in dichloromethane (DCM) underwent a bathochromic shift as the Hammett σp value of the para substituted phenyl groups increased from −0.28 to 0.81 (Table 1) [17,28]. As a result of introducing additional electron withdrawing groups on the aryl group, compounds 12i and 12j exhibited bathochromically shifted yellow and red fluorescence, respectively [28]. Moreover, the Stokes shifts of these 2-substituted TAPs were between 83 and 166 nm, which are rather large values. Notably, compounds 12f and 12i showed a strong positive solvatochromism as the emission maxima increased with 72 nm and 99 nm, respectively, when changing the solvent from benzene to acetone. The trends based on the Hammett values and the solvatochromic effect might be of use to predict the emission wavelengths of TAPs with other substituents at position 2 and in different solvents. Unfortunately, the quantum yields of the fluorescence of most 2-substituted TAPs were rather low (3–44%).

2.2.2. The 2,5-Disubstituted 1,3a,6a-Triazapentalenes

The 2,5-disubstituted 1,3a,6a-triazapentalenes were prepared via the general procedure by using 2-substituted 3-azido-2-methoxypropyl triflates 10b [27]. In this case, the aromatization failed when using triethylamine as the base. In addition, in the presence of DBU as a stronger base or in an acidic environment, elimination of the methoxy group did not happen. However, the elimination occurred by using KHMDS at −78 °C, and 2,5-disubstituted TAPs 13 were obtained successfully (Scheme 4) [27]. Nearly all reaction yields were good, except for the examples with a phenyl group at the C5 position (13d) or with a 4-nitrophenyl substituent at position 2 (13i). Note that the latter derivatives were prepared without heating to reflux temperature or by using lithium diethylamide base, respectively.
An interesting observation was that the quantum yields of fluorescence for 13ad were dramatically increased as a result of introducing a functional group at the C5 position of 2-cyanophenyl-TAP 12f, as shown in Table 2 [27]. Moreover, these functional groups at the C5 position had no obvious effect on the emission wavelengths, except for the introduction of a 5-cyano group that caused a hypsochromic effect on both the absorption and emission wavelengths. When changing the aryl substituent at the C2 position of different 5-methyl-TAPs, the quantum yields substantially increased when the Hammett values σp increased from 0 to 0.71, as shown in Table 3. For the 4-methoxyphenyl (σp = −0.28) and the 4-nitrophenyl (σp = 0.81) substituents, the quantum yields were only 0.02 and 0.03, respectively. Thus, for some examples, a relation could be noticed between the quantum yield of 2-arylated 5-methyl-TAPs and the Hammett parameter of the phenyl substituent.

2.2.3. The 2,4-Disubstituted 1,3a,6a-triazapentalenes

To investigate the effect of substituents at the C4 position, various 4-methyl and 4-phenyl-TAP analogs were synthesized by the Namba group (Scheme 5) [29]. The yields of the 4-methyl-TAP analogs were more variable (19–94%) (Table 4). On the other hand, the 4-phenyl-TAPs were obtained in moderate-to-high yields (50–88%) (Table 5). For some derivatives, the low yields were attributed to decomposition during purification. To expand the scope of 4-methyl-TAP analogs, 1,4-diethynylbenzene 9b and cyclic strained alkyne 9c were applied to synthesize 14a and 14b, respectively, via the reaction with 3-azido-3-methylpropane-1,2-diyl bistriflate. The designed compound 14a was not obtained as the reaction stopped after the mono-TAP was formed. This intermediate was readily decomposed during purification. Compound 14b was obtained successfully in 49% yield via the general procedure but without the use of a copper catalyst. For comparison, similar reactions were carried out to afford the corresponding 4-unsubstituted TAPs 12k and 12l in 46% and 51% yields, respectively.
Interestingly, the emission maxima of 4-phenyl-TAP (such as 14m, λem,max = 613 nm) and 4-methyl-TAP (such as 14e, λem,max = 611 nm) analogs were similar to each other [29]. Therefore, it could be concluded that the expansion of π–conjugation between the C4 phenyl and TAP core did not show an effect on the emission wavelength. To compare with 4-unsubstituted TAPs, the extinction coefficient (ε) values of 4-phenyl analogs were measured at slightly longer absorption wavelengths and larger ε values were observed, which may enhance the brightness as for 14j and 14k (Table 5). Remarkably, both a methyl and phenyl group at the C4 position could induce a redshift of the maximum emission wavelength.

2.2.4. The 2,6-Disubstituted 1,3a,6a-Triazapentalenes

To obtain the 2,6-disubstituted TAPs, the initial plan was to use the general procedure starting from 3-azido-1-methylpropane-1,2-diyl bistriflates and terminal alkynes. However, the methylazidoditriflate was not stable enough to prepare. In 2013, Namba et al. reported a Payne-type rearrangement of 1-(oxiranylmethyl)-1,2,3-triazoles [33]. Based on this earlier study, a reported procedure was developed for the synthesis of 2,6-disubstituted 1,3a,6a-triazapentalenes 21. The intermediate 20 was formed by the triflic acid-mediated epoxide-opening reaction, then followed by the subsequent reactions of acetylation and base-induced elimination (Scheme 6) [30]. Due to the poor stability of the 6-methyl-substituted TAPs, all reaction yields were relatively low (Table 6), while the more stable 6-(methoxycarbonyl)-TAP 23 was obtained in 40% yield. On the other hand, the 6-phenyl-TAP was not obtained after attempts under various conditions.
Introducing the methyl group at the C6 position of 2-substituted 1,3a,6a-triazapentalenes not only induced a long-wavelength shift of the emission maxima but also affected the quantum yields (Table 6) [30]. Nearly all the quantum yields were somewhat increased, except for compounds 21d and 21e. Notably, the methoxycarbonyl group at the C6 position (23) quenched the fluorescence. It was assumed that the electron withdrawing group disturbed the charge transfer between the TAP core and C2 substituents.

2.3. Gold-Catalyzed Cyclization of Propargyl-1,2,3-Triazoles

In 2010, Shi et al. reported an efficient method to synthesize propargyl-1,2,3-triazoles 24 via the iron-catalyzed alkylation with propargyl alcohols and found that the N2-substituted propargyl triazoles 24 could be further transformed via the intramolecular gold-catalyzed triazole-yne cyclization (Scheme 7) [34]. Later in 2014, the same group demonstrated that this cyclization resulted in the formation of TAPs 27 by using propargyl triazoles 24 bearing an electron withdrawing group (Scheme 7) [31]. The electron withdrawing group on the triazole ring, mainly ketones and esters, changed the electron density distribution of the intermediate bicyclic system. This electron density redistribution induced an effective regioselection followed by protodeauration to afford differently substituted triazapentalenes 27. In general, ester-substituted TAPs were obtained in slightly lower yields. However, the diester-substituted TAPs were shown to form in high yields (over 80%). Furthermore, starting from mono ester-substituted TAPs, 3-unsubstituted TAPs were obtained via LiOH-induced saponification/decarboxylation.
As mentioned by Hirobe et al. [26], the electron withdrawing group at the C3 position significantly improved the stability of the TAP core. In addition, the 2,3- bis(methoxycarbonyl)-TAP exhibited a quantum yield of fluorescence of 15%, which was much higher than 3-(methoxycarbonyl)-TAPs and 3-(4-toluoyl)-TAPs (lower than 1%).

2.4. Triazolization-Mediated Synthesis

In 2016, our group reported the synthesis of 3-arylated triazapentalene derivatives by using the multicomponent triazolization reaction followed by cyclization as shown in Scheme 8 [32]. Starting from 3-aminopropane-1,2-diol 28, acetophenones 29, and p-nitrophenyl azide [35], the intermediate 1,2,3-triazoles 30 were prepared. Then, the 3-(triazol-1-yl)propane-1,2-diols 30 underwent sequential substitution and elimination by treatment with triflic anhydride in the basic environment (pyridine/dichloromethane) to afford 3-substituted TAPs 31.
Compared to previous methods, this two-step pathway started from commercially available compounds and there was no need for toxic transition metal catalysts. However, only TAPs with electron poor aryl groups at the C3 position were successfully obtained.
The fluorescence properties of 3-substituted TAPs were studied in acetonitrile, DCM and toluene [32]. Surprisingly, compound 31a with a 4-nitrophenyl group at the C3 position showed no fluorescence, which was different from its fluorescent isomer 2-(4-nitrophenyl)-triazapentalene 12g. In contrast with the other 3-aryl-TAPs 31, compound 31a exhibited a longer absorption maximum wavelength and a broader absorption peak (Table 7). These properties of 31a might be due to the intramolecular charge transfer caused by the nitro group. Compared to the 2-cyanophenyl TAP 12f, the Stokes shift of compound 31b (63 nm) was relatively small in DCM, but the quantum yield of fluorescence was quite high (57%). The Stokes shifts of compounds 31b and 31c increased as the polarity of the solvent increased, and the full widths at half maximum of emission of compounds 31b and 31c were similar to each other. Remarkably, the quantum yield of the fluorescence of compound 31c was 79% in DCM, which was the highest quantum yield measured so far for any TAP derivative, although this was a lot less in the polar solvent acetonitrile (4%).

3. Post-Modifications

3.1. Acetylation and Nitrosation

Although 2-substituted TAPs 5 and 8 were sensitive to air, acetylation and nitrosation of these compounds could be carried out. The TAPs reacted at the C3 position, resulting in 3-acetyl and 3-nitroso derivatives in high yields (Scheme 9) [26]. The successful electrophilic substitution reactions clearly demonstrated the electron rich nature of the TAP core.

3.2. Linearly Bonded 1,3a,6a-Triazapentalene Dimers and Trimer

Starting from the azidotriflate 33 with protected alkyne function, a 2,5-disubstituted TAP with tert-butyldimethylsilyl ether (TBS) protecting group was synthesized via click reaction followed by cyclization. The azidotriflate 33 was prepared via a multistep synthesis [36]. After removing the TBS group, the monoethyl-substituted triazapentalene 34 was applied as the starting material together with one more equivalent of 33 in a reiteration of this TAP formation, to develop the linearly bonded oligomeric systems 35 (Scheme 10) [36]. The TAP dimers (n = 2) with different substituents at the C2 position were reported by the Namba group, including a 2-unsubstituted TAP dimer. Unfortunately, the TAP trimers (n = 3) were, in general, too difficult to obtain due to decomposition during the elimination reactions (Table 8). An exception was the derivative with a tridecyl group at the C2 position.
The properties of TAP monomers, TAP dimers, and the TAP trimer were rather similar in the diluted solution in DCM, showing that introducing additional TAP rings had no drastic effect on the fluorescence characteristics [36]. Interestingly, the linearly bonded TAP dimer 35 (n = 2, R = Ph) showed different fluorescence properties when varying the concentration, which suggested changes in the aggregation state. The phenyl-TAP-dimer showed mechanochromic fluorescence in the solid phase and a fluorescence wavelength redshift while going from the crystalline to the amorphous state upon grinding. Emission lifetimes were determined for the solid dimer 35 (n = 2, R = Ph) at 540 nm before (λem,max = 535 nm) and after grinding (λem,max = 590 nm), and were found to be 4.9 and 1.2, respectively. Notably, density functional theory (DFT) calculations verified the planar form of trimer-TAP (R = C13H27).

3.3. Azo-Coupling Reaction of 3-aryl-1,3a,6a-Triazapentalene

Starting from TAP 31c, the reaction with benzenediazonium tetrafluoroborate was studied by our group in an attempt to introduce a phenyl group after radical coupling (Scheme 11) [37]. Surprisingly, azo-coupling was observed instead of CH-arylation, which was most probably due to the marked nucleophilic character of the triazapentalene. It was intriguing that under the reaction circumstances, a rearranged 2-aryl-TAP 37 was readily formed and isolated as the major product, accompanied by an azo-coupled 3-aryl-TAP 36 as the minor product. The molecular structures of the products were elucidated using single-crystal X-ray diffraction analysis. A mechanism towards TAP 37 involving the formation of an open chain nitrilimine and alternative ring closure was proposed. Different attempts were carried out to reduce azo compound 37, which led to cleavage of the TAP core rather than the formation of the amino derivative.

4. Applications

The fluorescent TAP core has been studied by the Namba group as an element of biological imaging probes and sensors. All TAP products discussed within this section were synthesized via the CuAAC-based strategy.
The first application concerns the use of TAP as a fluorescent probe for live cell imaging [28]. Compound 12i was selected as the fluorescent dye due to its small but significant solubility in water and because it combines a long fluorescent wavelength with acceptable stability under UV irradiation (Scheme 12). After treatment with a DMSO solution of the fluorescent dye 12i, staining of Hela cells was clearly observed with fluorescence microscopy and no cytotoxic effect was seen during the observation period.
Then, the TAP 12i was developed as a fluorescent reagent to label glycine ethyl ester and tripeptide Gly-Pro-Leu [28]. By treating methyl ester TAP 12i with lithium hydroxide, a benzoic acid derivative was obtained that was directly converted into an activated N-hydroxysuccinimide (NHS) ester 38. As the purification from the DCC-derived urea was troublesome, instead, polymer-supported DCC was used and could be filtered off to give pure reactive ester 38. Subsequently, compound 38 was reacted with glycine ethyl ester and tripeptide Gly-Pro-Leu to obtain the labeled glycine 39 and tripeptide 40, respectively. Compounds 39 and 40 showed the same fluorescence maximum at 567 nm with 37% and 24% fluorescence quantum yields in DCM, respectively. The fluorescence measurements for these compounds in water demonstrated decreased Stokes shifts and quantum yields.
The second application was based on compound 12e (Figure 2), which showed high fluorescence intensity in phosphate-buffered saline (PBS) and was applied as a fluorescent probe to observe cellular differentiation processes in various living cells [38]. After treatment with a PBS solution of 12e, cytoplasmic and nuclear morphological changes during the differentiation processes were monitored by fluorescence microscopy. It was found that the fluorescence probe 12e had no toxicity, neither was there an effect on the cellular differentiation processes, and the probe could be easily washed away from the cells that can continue to culture for following studies.
In a third application, TAP analogs of biphenyl-type kinesin spindle protein (KSP) inhibitors 41 and 42 (Figure 3) were prepared and investigated as bifunctional fluorescent probes [39]. Both analogs showed inhibitory activity against KSP ATPase, although 42 was more potent (half maximal inhibitory concentration (IC50) was 6.8 µM). Further microscopic studies were carried out with 42 in cultured cells in order to visualize the intracellular distribution. The partial colocalization of compound 42 with KSP, combined with its inhibitory activity, demonstrated the potency of the TAP fluorophore to be used as a probe for the visualization of bioactive substances and their targets.
Most recently, a compact vinyl ketone functionalized TAP 45 was cleverly designed by Namba et al. as a thiol-specific fluorescent labeling reagent [40]. Starting from the previously reported 2-methoxycarbonyl-TAP 43, the electrophilic α,β-unsaturated ketone TAP 45 was prepared via a high-yielding multistep synthesis involving Weinreb amide 44 (Scheme 13). The 2-vinyl ketone-TAP 45 was then reacted with various thiols via thiol Michael additions to obtain compounds 46. Remarkably, the fluorescence intensity of 45 was turned off due to the conjugation of the vinyl ketone at the C2 position. After the addition of the thiol group, this conjugation was interrupted, and the fluorescence of compound 46 was turned on again while also exhibiting shorter emission wavelengths as compared to 45. A water-soluble R8 peptide was also successfully labeled in a phosphate buffer (pH 7). Although no fluorescence was observed in water, the labeled peptide became luminescent after uptake and localization in the hydrophobic regions of A549 cells. Advantageously, the vinyl ketone TAP did not cause any background fluorescence and was not found to be cytotoxic. Next, a captopril-TAP conjugate was prepared for drug imaging. Captopril is a cysteine derivative that inhibits angiotensin converting enzyme (ACE) and has been used for the treatment of hypertensive patients. The inhibitory activity and confocal laser microscope imaging studies in vascular endothelial cells demonstrated that the fluorophore had no impact on the activity of captopril and that the fluorophore could be used as a probe for mechanistic studies.
In a final application, TAP derivative 51 was used as a fluorescent sensor for iron (Scheme 14) [41]. Starting with a protected catechol-containing alkyne 48 and azide 10a, TAP 49 was obtained via the CuAAC reaction strategy. In order to increase the stability, an acetyl group was introduced into compound 49 at the C3 position through acylation. The acetylated compound 50 was further conjugated to serine trimer 47 by saponification and amide coupling. After deprotection with HCl, the TAP labeled enterobactin 51 was obtained. The influence of iron on the fluorescent properties of sensor 51 was studied with Fe(acac)3 as an Fe3+ ion source at different concentrations. When increasing the amount of Fe3+ in a DMSO solution of 51, the fluorescence intensity was decreased gradually, with complete disappearance at 1.2 equivalents of Fe(acac)3. The emission maximum did not change. In DMF and tert-butanol, a similar phenomenon was observed. Fourth-period metals also caused a clear decrease in fluorescence intensity, although no complete quenching was observed, even while adding 5.0 equivalents. Thus, 1,3a,6a-triazapentalene-labeled enterobactin 51 was shown to be a selective and highly sensitive fluorescence-quenching sensor for iron (III).

5. Conclusions

In this mini review, we have discussed the different synthetic methodologies of bicyclic 1,3a,6a-triazapentalenes. An alternative to the earlier synthesis from pyrazoles and aminating reagents was provided by the CuAAC-based strategy, which could be used to synthesize a wide scope of 2-substituted TAPs. The gold-catalyzed cyclization pathway afforded excellent yields of highly functionalized TAPs with electron withdrawing functional groups at the C3 position. Unfortunately, the starting materials for these methods often need to be prepared via a multistep synthesis. The triazolization-mediated synthesis provided access to 2-unsubstituted TAPs from readily available starting materials. Therefore, this was complementary to the previous strategies.
As a result of the profound studies by Namba et al., the substituent effects on the properties of TAP are known and could allow one to design the fluorophores according to the requirements of a particular application. For example, the stability of the TAP core could at first be ensured by introducing an electron withdrawing group at the C3 position, while the fluorescence wavelength could be adjusted by variation of the substituent at the C2 position. Further adjustments of the properties could be made with the substituent at the C4, C5 or C6 position. For instance, the extinction coefficient and therefore brightness of TAPs could be increased by introducing a substituent at the C4 position. For the TAP compounds that require high quantum yields, often it is a good idea to introduce a substituent at the C5 or C6 position.
Applications of TAPs were mainly focused on live-cell fluorescence imaging, in particular drug imaging, although an application as iron chemosensor was also reported. The small size of the TAP core is often mentioned as an advantage compared to other fluorescent probes. Up to this moment, reports about TAP probes and sensors have been limited to 2-substituted TAPs, which are obtained via the CuAAC method. Problems that often occur and still need to be solved are poor solubility and weak fluorescence intensity of the TAP probes in water.
We are only at the start of the applications of this new and compact fluorophore TAP. Hopefully, this review will stimulate further investigations.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Acknowledgments

Yingchun Wang acknowledges the China Scholarship Council for a doctoral fellowship (201706920044); Tomas Opsomer thanks the FWO-Vlaanderen for a doctoral fellowship (1154419N) and KU Leuven for a postdoctoral mandate (PDM/20/091). Wim Dehaen acknowledges financial support from KU Leuven (Project C14/19/78).

Conflicts of Interest

The authors declare no conflict of interest.

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Chemosensors 09 00016 g001 550
Figure 1. Numbering of the 1,3a,6a-triazapentalene (TAP) core (a) and the general structures of non-fused TAPs (b) and (hetero)aryl-fused TAPs (c).
Figure 1. Numbering of the 1,3a,6a-triazapentalene (TAP) core (a) and the general structures of non-fused TAPs (b) and (hetero)aryl-fused TAPs (c).
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Chemosensors 09 00016 sch001 550
Scheme 1. Synthesis of 2-methyl-TAP 5 and 2-phenyl-TAP 8.
Scheme 1. Synthesis of 2-methyl-TAP 5 and 2-phenyl-TAP 8.
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Chemosensors 09 00016 sch002 550
Scheme 2. CuAAC-based synthesis of 3-unsubstituted TAPs 11.
Scheme 2. CuAAC-based synthesis of 3-unsubstituted TAPs 11.
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Chemosensors 09 00016 sch003 550
Scheme 3. The synthesis of 2-substituted TAPs 12 and the parent TAP 12b.
Scheme 3. The synthesis of 2-substituted TAPs 12 and the parent TAP 12b.
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Chemosensors 09 00016 sch004 550
Scheme 4. Synthesis of 2,5-disubstituted TAPs 13.
Scheme 4. Synthesis of 2,5-disubstituted TAPs 13.
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Chemosensors 09 00016 sch005 550
Scheme 5. The synthesis of 2,4-disubstituted TAPs 14 and corresponding 4-unsubstituted TAPs. R4 = Me or Ph.
Scheme 5. The synthesis of 2,4-disubstituted TAPs 14 and corresponding 4-unsubstituted TAPs. R4 = Me or Ph.
Chemosensors 09 00016 sch005
Chemosensors 09 00016 sch006 550
Scheme 6. Synthesis of 2,6-disubstituted TAPs 21 and 23.
Scheme 6. Synthesis of 2,6-disubstituted TAPs 21 and 23.
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Chemosensors 09 00016 sch007 550
Scheme 7. Gold-mediated synthesis of TAPs 27.
Scheme 7. Gold-mediated synthesis of TAPs 27.
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Chemosensors 09 00016 sch008 550
Scheme 8. The synthesis of 3-substituted TAPs 31.
Scheme 8. The synthesis of 3-substituted TAPs 31.
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Chemosensors 09 00016 sch009 550
Scheme 9. The acetylation and nitrosation.
Scheme 9. The acetylation and nitrosation.
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Chemosensors 09 00016 sch010 550
Scheme 10. Synthesis of TAP dimers (n = 2) and trimer (n = 3). (a) CuI (5 mol%), BDMAEE (5 mol%), TEA, THF; (b) THF, reflux or 50 °C; (c) KHMDS, −78 °C; (d) TBAF, THF, 0 °C; (e) LiNEt2, −78 °C (pyrrolidine lithium salt used for the synthesis of the TAP trimer).
Scheme 10. Synthesis of TAP dimers (n = 2) and trimer (n = 3). (a) CuI (5 mol%), BDMAEE (5 mol%), TEA, THF; (b) THF, reflux or 50 °C; (c) KHMDS, −78 °C; (d) TBAF, THF, 0 °C; (e) LiNEt2, −78 °C (pyrrolidine lithium salt used for the synthesis of the TAP trimer).
Chemosensors 09 00016 sch010
Chemosensors 09 00016 sch011 550
Scheme 11. Azo coupling of 3-aryl-TAP 31c towards 6-azo derivative 36 and rearranged 4-phenylazo-2-aryl-TAP 37. Ar = 4-MeOCO-C6H4.
Scheme 11. Azo coupling of 3-aryl-TAP 31c towards 6-azo derivative 36 and rearranged 4-phenylazo-2-aryl-TAP 37. Ar = 4-MeOCO-C6H4.
Chemosensors 09 00016 sch011
Chemosensors 09 00016 sch012 550
Scheme 12. Synthesis of TAP-labeled labeled glycine 39 and tripeptide 40 and properties in DCM. a Measured in water. Su = succinimide.
Scheme 12. Synthesis of TAP-labeled labeled glycine 39 and tripeptide 40 and properties in DCM. a Measured in water. Su = succinimide.
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Chemosensors 09 00016 g002 550
Figure 2. The 2-([1,1’-Biphenyl]-4-yl)-TAP 12e.
Figure 2. The 2-([1,1’-Biphenyl]-4-yl)-TAP 12e.
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Figure 3. Structure and properties of 2-(4-(trifluoromethyl)phenyl)-TAP 41 and 2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)-TAP 42 in DCM.
Figure 3. Structure and properties of 2-(4-(trifluoromethyl)phenyl)-TAP 41 and 2-(4’-(trifluoromethyl)-[1,1’-biphenyl]-4-yl)-TAP 42 in DCM.
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Scheme 13. The synthesis of TAP labeling reagent 45 and thiol adducts 46.
Scheme 13. The synthesis of TAP labeling reagent 45 and thiol adducts 46.
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Chemosensors 09 00016 sch014 550
Scheme 14. Synthesis of fluorescence quenching sensor 51. (a) LiOH∙H2O, dioxane/H2O, 55 °C; (b) 47 (1.0 equivalent), DMTMM, DIPEA, MeOH; (c) 0.5 M HCl, iPrOH. a Measured in DMSO.
Scheme 14. Synthesis of fluorescence quenching sensor 51. (a) LiOH∙H2O, dioxane/H2O, 55 °C; (b) 47 (1.0 equivalent), DMTMM, DIPEA, MeOH; (c) 0.5 M HCl, iPrOH. a Measured in DMSO.
Chemosensors 09 00016 sch014
Table
Table 1. Fluorescence properties and reaction yields of selected 2-substituted TAPs 12c–g in DCM.
Table 1. Fluorescence properties and reaction yields of selected 2-substituted TAPs 12c–g in DCM.
Chemosensors 09 00016 i001R2
Chemosensors 09 00016 i002 Chemosensors 09 00016 i003 Chemosensors 09 00016 i004 Chemosensors 09 00016 i005 Chemosensors 09 00016 i006 Chemosensors 09 00016 i007 Chemosensors 09 00016 i008 Chemosensors 09 00016 i009
Compound12c12d12e12f12g12h12i12j
Yield (%)8956817096737172
λabs,max (nm)326330345381412376420466
Hammett σp0−0.280.040.710.81-a-a-a
λem,max (nm)419413456509556510572632
Stokes shift (nm)9383111128144134152166
φF (%)36241816443410
a No data available.
Table
Table 2. Fluorescence properties and reaction yields of 5-substituted 2-cyanophenyl-TAPs 13a–d in DCM.
Table 2. Fluorescence properties and reaction yields of 5-substituted 2-cyanophenyl-TAPs 13a–d in DCM.
Chemosensors 09 00016 i010R5
MeOMe-CNPhH
R2 = C6H4CN13a13b13c13d12f
Yield (%)6360571970
λabs,max (nm)385378360383381
λem,max (nm)518505453506509
Stokes shift (nm)13312793123128
φF (%)5557454818
Table
Table 3. Fluorescence properties and reaction yields of 2-substituted 5-methyl-TAPs 13e–i in DCM.
Table 3. Fluorescence properties and reaction yields of 2-substituted 5-methyl-TAPs 13e–i in DCM.
Chemosensors 09 00016 i011R2
Chemosensors 09 00016 i012 Chemosensors 09 00016 i013 Chemosensors 09 00016 i014 Chemosensors 09 00016 i015 Chemosensors 09 00016 i016
R5 = CH313e13f13g13h13i
Yield (%)8172596327
λabs,max (nm)340340370385370
Hammett σp0−0.280.040.710.81
λem,max (nm)422 (419) a421 (413) a466 (456) a518 (509) a575 (556) a
Stokes shift (nm)828196133205
φF (%)7 (3) b3 (6) b27 (24) b55 (18) b2 (16) b
a Fluorescence maximum of corresponding 5-unsubstituted analog. b Fluorescence quantum yield of corresponding 5-unsubstituted analog.
Table
Table 4. Fluorescence properties and reaction yields of 2-substituted 4-methyl-TAPs 14c–h in DCM.
Table 4. Fluorescence properties and reaction yields of 2-substituted 4-methyl-TAPs 14c–h in DCM.
Chemosensors 09 00016 i017R2
-COOMe Chemosensors 09 00016 i018 Chemosensors 09 00016 i019 Chemosensors 09 00016 i020 Chemosensors 09 00016 i021 Chemosensors 09 00016 i022
R4 = CH314c14d14e14f14g14h
Yield (%)94 (90) a82 (73) a19 (71) a60 (74) a28 (81) a50(40) a
λabs,max (nm)354 (342) b380 (376) b436 (420) b356 (358) b360 (345) b393 (379) b
λem,max (nm)456 (431) c553 (521) c611 (572) c485 (460) c491 (456) c558 (525) c
Stokes shift (nm)105173175129131165
φF (%)24 (18) d56 (44) d11 (34) d8 (35) d40 (24) d40 (43) d
a Reaction yield of 4-unsubstituted analog. b Absorption maximum of corresponding 4-unsubstituted analog. c Fluorescence maximum of corresponding 4-unsubstituted analog. d Quantum yield of corresponding 4-unsubstituted analog.
Table
Table 5. Fluorescence properties and reaction yields of 2-substituted 4-phenyl-TAPs 14i–o in DCM.
Table 5. Fluorescence properties and reaction yields of 2-substituted 4-phenyl-TAPs 14i–o in DCM.
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-COOMe Chemosensors 09 00016 i024 Chemosensors 09 00016 i025 Chemosensors 09 00016 i026 Chemosensors 09 00016 i027 Chemosensors 09 00016 i028 Chemosensors 09 00016 i029
R4 = Ph14i14j14k14l14m14n14o
Yield (%)87708281887250
λabs,max (nm)358 (342) a387 (381) a383 (376) a342 (358) a432 (420) a369 (345) a378 (358) a
λem,max (nm)459 (431) b542 (509) b548 (521) b481 (460) b613 (572) b482 (456) b554 (525) b
Stokes shift (nm)101155165139181113176
φF (%)9 (18) c46 (15) c36 (44) c8 (35) c7 (34) c10 (20) c21 (43) c
ε (dm3 mol−1 cm−1)10,648 (2691) d6918 (3032) d7500 (1230) d19,822 (4213) d4560 (631) d19,409 (5011) d5497 (2542) d
a Absorption maximum of corresponding 4-unsubstituted analog. b Fluorescence maximum of corresponding 4-unsubstituted analog. c Quantum yield of corresponding 4-unsubstituted analog. d Extinction coefficient value of corresponding 4-unsubstituted analog.
Table
Table 6. Fluorescence properties and reaction yields of selected 2-substituted 6-methyl-TAPs 21a–e in DCM.
Table 6. Fluorescence properties and reaction yields of selected 2-substituted 6-methyl-TAPs 21a–e in DCM.
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Chemosensors 09 00016 i031 Chemosensors 09 00016 i032 Chemosensors 09 00016 i033 Chemosensors 09 00016 i034-C13H27
R6 = CH321a21b21c21d21e
Yield (%)2426371814
λabs,max (nm)390 (381) a341 (326) a362 (345) a400 (390) a357 (334) a
λem,max (nm)545 (509) b435 (419) b493 (456) b654 (608) b487 (482) b
Stokes shift (nm)15594131254130
φF (%)26 (15) c17 (3) c24 (20) c2 (20) c1 (4) c
a Absorption maximum of the corresponding 6-unsubstituted analog. b Fluorescence maximum of the corresponding 6-unsubstituted analog. c Quantum yield of corresponding to the 6-unsubstituted analog.
Table
Table 7. Fluorescent properties and reaction yields of 3-substituted TAPs 31 in DCM.
Table 7. Fluorescent properties and reaction yields of 3-substituted TAPs 31 in DCM.
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Chemosensors 09 00016 i036 Chemosensors 09 00016 i037 Chemosensors 09 00016 i038
Compound31a31b31c
Yield (%)697670
λabs,max (nm)475401399
λem,max (nm)-a464476
Stokes shift (nm)-a6377
fwhmem (cm−1)-a34953575
φF (%)-a5779
a No data available.
Table
Table 8. Structures and reaction yields of linearly bonded TAPs 35.
Table 8. Structures and reaction yields of linearly bonded TAPs 35.
Chemosensors 09 00016 i039R, Yield (%)
C13H27 Chemosensors 09 00016 i040 Chemosensors 09 00016 i041 Chemosensors 09 00016 i042TBS
n = 15253645969
n = 27531591738
n = 342-a-a-a-b
a Unsuccessful synthesis from dimer TAP. b Decomposed during purification.
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Wang, Y.; Opsomer, T.; Dehaen, W. Bicyclic 1,3a,6a-Triazapentalene Chromophores: Synthesis, Spectroscopy and Their Use as Fluorescent Sensors and Probes. Chemosensors 2021, 9, 16. https://doi.org/10.3390/chemosensors9010016

AMA Style

Wang Y, Opsomer T, Dehaen W. Bicyclic 1,3a,6a-Triazapentalene Chromophores: Synthesis, Spectroscopy and Their Use as Fluorescent Sensors and Probes. Chemosensors. 2021; 9(1):16. https://doi.org/10.3390/chemosensors9010016

Chicago/Turabian Style

Wang, Yingchun, Tomas Opsomer, and Wim Dehaen. 2021. "Bicyclic 1,3a,6a-Triazapentalene Chromophores: Synthesis, Spectroscopy and Their Use as Fluorescent Sensors and Probes" Chemosensors 9, no. 1: 16. https://doi.org/10.3390/chemosensors9010016

APA Style

Wang, Y., Opsomer, T., & Dehaen, W. (2021). Bicyclic 1,3a,6a-Triazapentalene Chromophores: Synthesis, Spectroscopy and Their Use as Fluorescent Sensors and Probes. Chemosensors, 9(1), 16. https://doi.org/10.3390/chemosensors9010016

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