Non-K Region Disubstituted Pyrenes (1,3-, 1,6- and 1,8-) by (Hetero)Aryl Groups—Review

Disubstituted pyrenes at the non-K region by the same or different (hetero)aryl groups have proven to be an increasingly interesting area of research for scientists over the last decade due to their optical and photophysical properties. However, in this area, there is no systematization of the structures and synthesis methods nor their limitations. In this review, all approaches to the synthesis of these compounds, starting from the commercially available pyrene are described. Herein, the ways of obtaining of disubstituted intermediates based on bromination and acylation reaction are presented. This is crucial in the determination of the possibility of further functionalization by using coupling, cycloaddition, condensation, etc. reactions. Moreover, the application of disubstituted pyrenes in the synthesis of 1,3,6,8-tetrasubstituted was also reviewed. This review describes the directions of research on chemistry of disubstituted pyrenes.


Introduction
Despite the topic of pyrene derivatives having already been covered extensively by scientific literature, it still proves to be a popular subject of new research [1][2][3]. Without a doubt, pyrene and its derivatives exhibit intriguing properties. Multiple systematic studies have shown this already, yet still, new areas of interest such as the non-K region (the positions 4-, 5-, 9-, and 10-of pyrene are described as K-region due to carcinogenic effect of pyrene upon its oxidation) disubstituted by aryl or heteroaryl groups at pyrenes (1,3-, 1,6-, and 1,8-) are being elucidated. Disubstituted pyrenes of this type are interesting in themselves and can act as substrates in the synthesis of the other molecules that also exhibit expected properties. The vast majority of disubstituted pyrenes can be applied in organic electronics in materials such as organic light-emitting diodes (OLEDs) [4][5][6][7][8][9], organic field-effect transistors (OFETs) [10,11], and solar cells [12] but also in the synthesis of nanographenes [13], metal cages [14,15], and many others. A wide spectrum of methods for the synthesis of the reported compounds exists, though a fundamental problem lies within the methods' ordering. Nonetheless, in 2011, Klaus Müllen and Teresa M. Figueira-Duarte presented a review article about pyrene-based materials for organic electronics [1], in 2014, Anthony P. Davis et al. systematized the ways of synthesis of substituted pyrenes by indirect methods [16], and in 2016, Xing Feng et al. described functionalization of pyrene in detail, especially tetrasubstituted pyrenes at non-K and K-region, which are suitable as luminescent materials [2]. However, the systematization of 1,3-, 1,6-, and 1,8-disubstituted pyrenes is still lacking.
Despite the hard work of the scientists mentioned above, an issue concerning the description of substituted positions in recently published papers on pyrenes becomes apparent. Indeed, it could just be a result of getting used to an idea replicated in literature. However, if a recognized misconception is In the presented review, the ways of synthesis of 1,3-, 1,6-and 1,8-disubstituted pyrenes starting from pyrene, followed by the intermediates such as dibromo, diacetyl, and boroorganic pyrenes suitable for further functionalization in pure form or as mixtures are described as reported in the literature. Moreover, the possibility of the application of disubstituted pyrenes in the synthesis of 1,3,6,8-tetrasubstituted is also presented.

Dibromopyrenes
The most significant role in the synthesis of disubstituted pyrenes plays its dibromo derivatives, which are suitable for the further functionalization in various reactions such as substitution and coupling reactions (Suzuki-Miyaura, Stille, and Sonogashira). The electronic structure of pyrene causes a bromination reaction, and the derivatives containing bromine at positions 1-, 3-, 6-, 8-(non-K region) can be preferably obtained. Only the application of appropriate reaction conditions allows us to obtain dibromopyrenes with the expected substitution pattern.

1,6-And 1,8-dibromopyrene
The interest of the synthesis and obtaining of the 1,6-and 1,8-dibromopyrene (Scheme 1) in its pure form dates back to early 1970s of the previous century when J. Grimshaw and J. Trocha-Grimshaw reported a procedure for synthesis that used slow addition of bromine solution in carbon tetrachloride into pyrene 1 solution in the same solvent, which resulted in the isomers that were separated by crystallization from toluene or mixture of benzene-hexane with 44% yield 1,6-isomer 2 and 45% yield 1,8-isomer 3 [18].  In the presented review, the ways of synthesis of 1,3-, 1,6-and 1,8-disubstituted pyrenes starting from pyrene, followed by the intermediates such as dibromo, diacetyl, and boroorganic pyrenes suitable for further functionalization in pure form or as mixtures are described as reported in the literature. Moreover, the possibility of the application of disubstituted pyrenes in the synthesis of 1,3,6,8-tetrasubstituted is also presented.

Dibromopyrenes
The most significant role in the synthesis of disubstituted pyrenes plays its dibromo derivatives, which are suitable for the further functionalization in various reactions such as substitution and coupling reactions (Suzuki-Miyaura, Stille, and Sonogashira). The electronic structure of pyrene causes a bromination reaction, and the derivatives containing bromine at positions 1-, 3-, 6-, 8-(non-K region) can be preferably obtained. Only the application of appropriate reaction conditions allows us to obtain dibromopyrenes with the expected substitution pattern.

1,6-And 1,8-dibromopyrene
The interest of the synthesis and obtaining of the 1,6-and 1,8-dibromopyrene (Scheme 1) in its pure form dates back to early 1970s of the previous century when J. Grimshaw and J. Trocha-Grimshaw reported a procedure for synthesis that used slow addition of bromine solution in carbon tetrachloride into pyrene 1 solution in the same solvent, which resulted in the isomers that were separated by crystallization from toluene or mixture of benzene-hexane with 44% yield 1,6-isomer 2 and 45% yield 1,8-isomer 3 [18]. In the presented review, the ways of synthesis of 1,3-, 1,6-and 1,8-disubstituted pyrenes starting from pyrene, followed by the intermediates such as dibromo, diacetyl, and boroorganic pyrenes suitable for further functionalization in pure form or as mixtures are described as reported in the literature. Moreover, the possibility of the application of disubstituted pyrenes in the synthesis of 1,3,6,8-tetrasubstituted is also presented.

Dibromopyrenes
The most significant role in the synthesis of disubstituted pyrenes plays its dibromo derivatives, which are suitable for the further functionalization in various reactions such as substitution and coupling reactions (Suzuki-Miyaura, Stille, and Sonogashira). The electronic structure of pyrene causes a bromination reaction, and the derivatives containing bromine at positions 1-, 3-, 6-, 8-(non-K region) can be preferably obtained. Only the application of appropriate reaction conditions allows us to obtain dibromopyrenes with the expected substitution pattern.

1,6-And 1,8-dibromopyrene
The interest of the synthesis and obtaining of the 1,6-and 1,8-dibromopyrene (Scheme 1) in its pure form dates back to early 1970s of the previous century when J. Grimshaw and J. Trocha-Grimshaw reported a procedure for synthesis that used slow addition of bromine solution in carbon tetrachloride into pyrene 1 solution in the same solvent, which resulted in the isomers that were separated by crystallization from toluene or mixture of benzene-hexane with 44% yield 1,6-isomer 2 and 45% yield 1,8-isomer 3 [18].
In the following years, various solvents, brominating agents, and reaction conditions were used. The vast majority of reported procedures was focused on obtaining the pure 1,6-isomer (Table 1). It can be noted that, in the case of carbon disulfide used as a solvent, the 1,8-isomer is obtained with the high yield ~85%. What is more, in other cases, almost the same reaction conditions resulted in the products with yields varying about 40%, which means the main problem is connected with the purification of the crude mixture after the reaction's completion.  In the following years, various solvents, brominating agents, and reaction conditions were used. The vast majority of reported procedures was focused on obtaining the pure 1,6-isomer (Table 1). It can be noted that, in the case of carbon disulfide used as a solvent, the 1,8-isomer is obtained with the high yield~85%. What is more, in other cases, almost the same reaction conditions resulted in the products with yields varying about 40%, which means the main problem is connected with the purification of the crude mixture after the reaction's completion. The other approach to the synthesis of 1,6-and 1,8-dibromopyrene presented in the literature is based on the synthesis in which the starting material 1-bromopyrene 4 is used (Scheme 2). 1-Bromopyrene can be successfully obtained with the high yield up to 96% by bromination of pyrene by the mixture HBr/H 2 O 2 [34]. The other approach to the synthesis of 1,6-and 1,8-dibromopyrene presented in the literature is based on the synthesis in which the starting material 1-bromopyrene 4 is used (Scheme 2). 1-Bromopyrene can be successfully obtained with the high yield up to 96% by bromination of pyrene by the mixture HBr/H2O2 [34]. The reaction conditions for the method mentioned above of obtaining of 1,6-and 1,8dibromopyrene are discussed in the literature in two publications. The first used a mixture of KBr/NaClO in HCl and MeOH solution, yielding in a mixture of products with 43% yield, whereas in the second case, bromine in dichloromethane obtained the target pure dibromopyrenes, with yields about 35% for every isomer (Table 2).

1,3-Dibromopyrene
As presented above, the synthesis of 1,6-and 1,8-dibromopyrenes is well described, whereas the 1,3-isomer is relatively unexplored. It is related to the difficulty of substitution of the pyrene structure due to the preference for electrophilic substitution at the 1,6-and 1,8-positions rather than the 1,3- The reaction conditions for the method mentioned above of obtaining of 1,6-and 1,8-dibromopyrene are discussed in the literature in two publications. The first used a mixture of KBr/NaClO in HCl and MeOH solution, yielding in a mixture of products with 43% yield, whereas in the second case, bromine in dichloromethane obtained the target pure dibromopyrenes, with yields about 35% for every isomer (Table 2).

1,3-Dibromopyrene
As presented above, the synthesis of 1,6-and 1,8-dibromopyrenes is well described, whereas the 1,3-isomer is relatively unexplored. It is related to the difficulty of substitution of the pyrene structure due to the preference for electrophilic substitution at the 1,6-and 1,8-positions rather than the 1,3-positions of pyrene. The determined spectroscopy yield of that isomer that is present as a byproduct of the bromination reaction equals 3% [36]. It causes that the substitution at positions 1 and 3 is only possible by the multistep reactions with the number of intermediates that contain the protecting groups at 7-position. 2-Pyrenecarboxylic acid 5 is suitable for that reaction and can be obtained in two multistep ways-starting from 4,5,9,10-tetrahydropyrene [37] or pyrene [38].
In the first approach reported in 1972 by Yu. E. Gerasimenko, 2-pyrenecarboxylic acid 5 was used in the bromination reaction, obtaining 1,3-dibromo-7-pyrenecarboxylic acid 6, which in further steps turned into 1,3-dibromo-7-aminopyrene 8, followed by the Sandmeyer reaction, which resulted in 1,3-dibromopyrene 9 with a 9.3% yield (Scheme 3) [39]. The other synthesis possibility was described by T. Nielsen et al., where 1,3-dibromopyrene was prepared from 1,3-dibromo-7-pyrenecarboxylic acid 6, previously obtained in alkaline hydrolysis of methyl 1,3-dibromopyrene-2-carboxylate. Intermediate 6 is used in the decarboxylation reaction with copper powder in boiling quinoline [40]. It should be noticed that authors describing the usage of 230 g of 6, resulting in 120 mg of 9. It can be supposed that 10 mL of quinoline and 100 mg of copper powder would be suitable for 230 mg of 6. I also conducted the reaction on the scale of 230 mg of 6 and 100 mg of Cu powder, but the target product was not obtained. Nontrivial synthesis of 1,3-dibromopyrene and the insufficiently reported protocols of its synthesis are also demonstrable by the lack of its application in the synthesis of 1,3-disubstituted pyrenes; only the approach with acylation of pyrene allows us to obtain the 1,3-disubstituted pyrenes, as described above. positions of pyrene. The determined spectroscopy yield of that isomer that is present as a byproduct of the bromination reaction equals 3% [36]. It causes that the substitution at positions 1 and 3 is only possible by the multistep reactions with the number of intermediates that contain the protecting groups at 7-position. 2-Pyrenecarboxylic acid 5 is suitable for that reaction and can be obtained in two multistep ways-starting from 4,5,9,10-tetrahydropyrene [37] or pyrene [38]. In the first approach reported in 1972 by Yu. E. Gerasimenko, 2-pyrenecarboxylic acid 5 was used in the bromination reaction, obtaining 1,3-dibromo-7-pyrenecarboxylic acid 6, which in further steps turned into 1,3-dibromo-7-aminopyrene 8, followed by the Sandmeyer reaction, which resulted in 1,3-dibromopyrene 9 with a 9.3% yield (Scheme 3) [39]. The other synthesis possibility was described by T. Nielsen et al., where 1,3-dibromopyrene was prepared from 1,3-dibromo-7pyrenecarboxylic acid 6, previously obtained in alkaline hydrolysis of methyl 1,3-dibromopyrene-2carboxylate. Intermediate 6 is used in the decarboxylation reaction with copper powder in boiling quinoline [40]. It should be noticed that authors describing the usage of 230 g of 6, resulting in 120 mg of 9. It can be supposed that 10 mL of quinoline and 100 mg of copper powder would be suitable for 230 mg of 6. I also conducted the reaction on the scale of 230 mg of 6 and 100 mg of Cu powder, but the target product was not obtained. Nontrivial synthesis of 1,3-dibromopyrene and the insufficiently reported protocols of its synthesis are also demonstrable by the lack of its application in the synthesis of 1,3-disubstituted pyrenes; only the approach with acylation of pyrene allows us to obtain the 1,3-disubstituted pyrenes, as described above.

Suzuki-Miyaura Coupling
Dibromopyrenes (1,6-and 1,8-isomer) are most often used in Suzuki-Miyaura coupling reaction in which they can react with (hetero)arylboronates or (hetero)arylboronic acids as well as after the functionalization as a boroorganic compounds. The synthesis of boroorganic derivatives of pyrene was described for 1,6-isomer (Schemes 4 and 5). 1,6-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrene 10 can be obtained in the commonly used reaction between the bromo derivative with bis(pinacolato)diboron in the presence of the catalyst [PdCl 2 (dppf)] and AcOK as a base, which results in a product with 99% yield [41]. Hikaru Suenaga et al. described the synthesis of 1,6-pyrenediyldiboronic acid that was obtained in a two-step reaction starting from 1,6-dibromopyrene and followed by 1,6-bis(trimethylsilyl)pyrene intermediate 11, which was suitable for obtaining the target acid 12 (Scheme 5). The authors did not report the yield of the compound 12 because it was used directly in the synthesis of pyrene-1,6diyldiboronic acid dimethyl ester, which was obtained with a 61% yield [30].

Pyrene Derivative Acting as a Boroorganic Compound
The application of the boroorganic derivative of pyrene 10 was presented by Long Chen and coworkers. Molecule 10 was applied in the reaction with methyl 2-iodobenzoate with the catalytic system [Pd(PPh3)4]/K2CO3 in THF/H2O, which resulted in the derivative 13 with 49% yield (Scheme 6) [10]. This compound was used further in the synthesis of the angularly fused bistetracene. Compound 10 was also reacted with bromo derivatives of methyl benzo[b]thiophene-2-carboxylate or methyl thiophene-2-carboxylate that yielded 14 (59%) and 15 (30%), which were used in the synthesis of bisthienoacenes [42].  Hikaru Suenaga et al. described the synthesis of 1,6-pyrenediyldiboronic acid that was obtained in a two-step reaction starting from 1,6-dibromopyrene and followed by 1,6-bis(trimethylsilyl)pyrene intermediate 11, which was suitable for obtaining the target acid 12 (Scheme 5). The authors did not report the yield of the compound 12 because it was used directly in the synthesis of pyrene-1,6diyldiboronic acid dimethyl ester, which was obtained with a 61% yield [30].

Pyrene Derivative Acting as a Boroorganic Compound
The application of the boroorganic derivative of pyrene 10 was presented by Long Chen and coworkers. Molecule 10 was applied in the reaction with methyl 2-iodobenzoate with the catalytic system [Pd(PPh3)4]/K2CO3 in THF/H2O, which resulted in the derivative 13 with 49% yield (Scheme 6) [10]. This compound was used further in the synthesis of the angularly fused bistetracene. Compound 10 was also reacted with bromo derivatives of methyl benzo[b]thiophene-2-carboxylate or methyl thiophene-2-carboxylate that yielded 14 (59%) and 15 (30%), which were used in the synthesis of bisthienoacenes [42]. Hikaru Suenaga et al. described the synthesis of 1,6-pyrenediyldiboronic acid that was obtained in a two-step reaction starting from 1,6-dibromopyrene and followed by 1,6-bis(trimethylsilyl)pyrene intermediate 11, which was suitable for obtaining the target acid 12 (Scheme 5). The authors did not report the yield of the compound 12 because it was used directly in the synthesis of pyrene-1,6-diyldiboronic acid dimethyl ester, which was obtained with a 61% yield [30].

Pyrene Derivative Acting as a Boroorganic Compound
The application of the boroorganic derivative of pyrene 10 was presented by Long Chen and co-workers. Molecule 10 was applied in the reaction with methyl 2-iodobenzoate with the catalytic system [Pd(PPh 3 ) 4 ]/K 2 CO 3 in THF/H 2 O, which resulted in the derivative 13 with 49% yield (Scheme 6) [10]. This compound was used further in the synthesis of the angularly fused bistetracene. Compound 10 was also reacted with bromo derivatives of methyl benzo[b]thiophene-2-carboxylate or methyl thiophene-2-carboxylate that yielded 14 (59%) and 15 (30%), which were used in the synthesis of bisthienoacenes [42]. Hikaru Suenaga et al. described the synthesis of 1,6-pyrenediyldiboronic acid that was obtained in a two-step reaction starting from 1,6-dibromopyrene and followed by 1,6-bis(trimethylsilyl)pyrene intermediate 11, which was suitable for obtaining the target acid 12 (Scheme 5). The authors did not report the yield of the compound 12 because it was used directly in the synthesis of pyrene-1,6diyldiboronic acid dimethyl ester, which was obtained with a 61% yield [30].

Suzuki-Miyaura Coupling of Dibromopyrenes with (Hetero)Arylboronic Acids
Plenty of the reports are dedicated to the Suzuki-Miyaura coupling reactions where dibromopyrenes react with (hetero)arylboronic acids. The introduction of anthracen-9-yl motifs into a pyrene structure was presented by Jongwook Park et al., where [Pd(PPh3)4]/K2CO3 in PhMe/THF was used as a catalytic system (Scheme 9). It resulted in 1,6-di(anthracen-9-yl)pyrene 18 with a 66% yield, which was used in the preparation of organic emitter films [7].

Suzuki-Miyaura Coupling of Dibromopyrenes with (Hetero)Arylboronic Acids
Plenty of the reports are dedicated to the Suzuki-Miyaura coupling reactions where dibromopyrenes react with (hetero)arylboronic acids. The introduction of anthracen-9-yl motifs into a pyrene structure was presented by Jongwook Park et al., where [Pd(PPh 3 ) 4 ]/K 2 CO 3 in PhMe/THF was used as a catalytic system (Scheme 9). It resulted in 1,6-di(anthracen-9-yl)pyrene 18 with a 66% yield, which was used in the preparation of organic emitter films [7].
Due to the wide interest in organic semiconductors based on the expanded polyaromatic structures such as bistetracene and naphtho-tetracenone, molecule 13, which is suitable for their synthesis, was also obtained by Michel Frigoli and co-workers using 2-methoxycarbonylphenylboronic acid with catalytic system [Pd 2 (dba) 3 ]/K 3 PO 4 in PhMe with two kinds of phosphines-SPhos and XPhos (Scheme 10). [44,45] The results of the reactions did not show any differences in the yield of the product (88%) in reference to using phosphine. It should be noted that the presented method resulted in a product with a higher yield of about 39% in comparison to the report of Long Chen et al. [10]. PhMe, THF Scheme 9. Introduction of anthracen-9-yl motifs into pyrene structure by using the Suzuki-Miyaura coupling reaction [7].
Due to the wide interest in organic semiconductors based on the expanded polyaromatic structures such as bistetracene and naphtho-tetracenone, molecule 13, which is suitable for their synthesis, was also obtained by Michel Frigoli and co-workers using 2methoxycarbonylphenylboronic acid with catalytic system [Pd2(dba)3]/K3PO4 in PhMe with two kinds of phosphines-SPhos and XPhos (Scheme 10). [44,45] The results of the reactions did not show any differences in the yield of the product (88%) in reference to using phosphine. It should be noted that the presented method resulted in a product with a higher yield of about 39% in comparison to the report of Long Chen et al. [10]. Among the other important disubstituted pyrene derivatives that are necessary for the synthesis of nanographenes, 1,6-bis(2-formylphenyl)pyrene 19 plays an important role. The compound mentioned above was obtained by two research teams (Scheme 11). Both of them used catalytic system [Pd(PPh3)4]/K2CO3 but different solvents. Wenming Su et al. carried out the reaction in a mixture of THF/H2O which led to obtaining a product with a higher yield (84%) [46] in comparison to Konstantin Amsharov et al., who applied a mixture of PhMe/MeOH, obtaining a product with 61% yield [13]. Scheme 9. Introduction of anthracen-9-yl motifs into pyrene structure by using the Suzuki-Miyaura coupling reaction [7]. PhMe, THF Scheme 9. Introduction of anthracen-9-yl motifs into pyrene structure by using the Suzuki-Miyaura coupling reaction [7].
Due to the wide interest in organic semiconductors based on the expanded polyaromatic structures such as bistetracene and naphtho-tetracenone, molecule 13, which is suitable for their synthesis, was also obtained by Michel Frigoli and co-workers using 2methoxycarbonylphenylboronic acid with catalytic system [Pd2(dba)3]/K3PO4 in PhMe with two kinds of phosphines-SPhos and XPhos (Scheme 10). [44,45] The results of the reactions did not show any differences in the yield of the product (88%) in reference to using phosphine. It should be noted that the presented method resulted in a product with a higher yield of about 39% in comparison to the report of Long Chen et al. [10]. Among the other important disubstituted pyrene derivatives that are necessary for the synthesis of nanographenes, 1,6-bis(2-formylphenyl)pyrene 19 plays an important role. The compound mentioned above was obtained by two research teams (Scheme 11). Both of them used catalytic system [Pd(PPh3)4]/K2CO3 but different solvents. Wenming Su et al. carried out the reaction in a mixture of THF/H2O which led to obtaining a product with a higher yield (84%) [46] in comparison to Konstantin Amsharov et al., who applied a mixture of PhMe/MeOH, obtaining a product with 61% yield [13]. Scheme 10. Synthesis route to compound 13 [44,45].
Among the other important disubstituted pyrene derivatives that are necessary for the synthesis of nanographenes, 1,6-bis(2-formylphenyl)pyrene 19 plays an important role. The compound mentioned above was obtained by two research teams (Scheme 11). Both of them used catalytic system [Pd(PPh 3 ) 4 ]/K 2 CO 3 but different solvents. Wenming Su et al. carried out the reaction in a mixture of THF/H 2 O which led to obtaining a product with a higher yield (84%) [46] in comparison to Konstantin Amsharov et al., who applied a mixture of PhMe/MeOH, obtaining a product with 61% yield [13]. Scheme 11. Synthesis of 1,6-bis(2-formylphenyl)pyrene 19 [13,46].
In the case of synthesis of the compound containing phenylcoumarin 36, a small excess of tetrabutylammonium bromide (TBAB) (5% mol) was used, which significantly increased the yield of the reaction, and the product was obtained with a 76% yield (Scheme 21) [55].
In the case of synthesis of the compound containing phenylcoumarin 36, a small excess of tetrabutylammonium bromide (TBAB) (5% mol) was used, which significantly increased the yield of the reaction, and the product was obtained with a 76% yield (Scheme 21) [55]. The previously mentioned research team of Konstantin Amsharov also reported the synthesis of 1,6-bis(3-formylnaphthyl)pyrene, which, in contrast to disubstituted pyrene by 2-formylphenyl groups, was obtained in the Suzuki-Miyaura coupling reaction with 3-formylnaphthalene-2-boronic acid pinacol ester, which resulted in 37 with a higher yield of 76% (Scheme 22) [13]. The previously mentioned research team of Konstantin Amsharov also reported the synthesis of 1,6-bis(3-formylnaphthyl)pyrene, which, in contrast to disubstituted pyrene by 2-formylphenyl groups, was obtained in the Suzuki-Miyaura coupling reaction with 3-formylnaphthalene-2-boronic acid pinacol ester, which resulted in 37 with a higher yield of 76% (Scheme 22) [13]. In the case of synthesis of the compound containing phenylcoumarin 36, a small excess of tetrabutylammonium bromide (TBAB) (5% mol) was used, which significantly increased the yield of the reaction, and the product was obtained with a 76% yield (Scheme 21) [55]. The previously mentioned research team of Konstantin Amsharov also reported the synthesis of 1,6-bis(3-formylnaphthyl)pyrene, which, in contrast to disubstituted pyrene by 2-formylphenyl groups, was obtained in the Suzuki-Miyaura coupling reaction with 3-formylnaphthalene-2-boronic acid pinacol ester, which resulted in 37 with a higher yield of 76% (Scheme 22) [13]. In 2016, Jongwook Park and co-workers obtained 1,6-bis(3,5-diphenylbiphenyl-4-yl)pyrene 38 by using the system [Pd(OAc) 2 ]/Et 4 NOH in PhMe/THF what resulted in a product with low yield ≈ 7% (Scheme 23) [24]. Two years later, the same team presented extensive research with molecule 38 and its 1,8-and 4,9-isomers, which were synthesized starting from the pure dibromopyrene isomers using the catalytic system [Pd(OAc) 2 ]/Et 4 NOH in PhMe with the addition of triphenylphosphine (PPh 3 ). As a result of the reaction, molecule 38 was obtained with a 16% higher yield (23%), whereas the 1,8-isomer 39 had a 67% yield [25].

Mono-Suzuki-Miyaura Coupling
The pioneer in applying the mono-Suzuki-Miyaura coupling reactions in the synthesis of asymmetric 1,6-disubstituted pyrenes is Jongwook Park and co-workers, who presented in several papers derivatives of pyrene that contain at 1-position anthracen-9-yl motif (mostly substituted at 10position) and at 6-position various aryl/heteroaryl groups. The introduction of anthracen-9-yl group

Stille Coupling
In the area of disubstituted pyrene derivatives obtained using the Stille coupling reaction, there are only three papers in which authors used tributylstannyl derivatives of heteroaryls. The other approach to synthesis of previously mentioned 1,6-di(pyrid-2-yl)pyrene 16 was reported by Yu-Wu Zhong and Yan-Qin He in the presence of [PdCl2(PPh3)2], LiCl in PhMe, which resulted in a product with a significantly lower yield of 44% (Scheme 34). Synthesis using the Suzuki-Miyaura reaction obtained a product with a 96% yield (Scheme 7) [62].

Stille Coupling
In the area of disubstituted pyrene derivatives obtained using the Stille coupling reaction, there are only three papers in which authors used tributylstannyl derivatives of heteroaryls. The other approach to synthesis of previously mentioned 1,6-di(pyrid-2-yl)pyrene 16 was reported by Yu-Wu Zhong and Yan-Qin He in the presence of [PdCl 2 (PPh 3 ) 2 ], LiCl in PhMe, which resulted in a product with a significantly lower yield of 44% (Scheme 34). Synthesis using the Suzuki-Miyaura reaction obtained a product with a 96% yield (Scheme 7) [62].

Sonogashira Coupling
Applying the Sonogashira coupling reaction in the synthesis of disubstituted pyrenes containing directly substituted (hetero)aryl groups was described by Bo Song and co-workers [64]. The authors presented the synthetic route leading to 1,6-diethynylpyrene 60, which was obtained in a two-step reaction with a 44% yield. That compound was suitable for the Huisgen cycloaddition reaction, which allowed for the synthesizing of pyrene substituted by triazolyl groups 61 (Scheme 37). It should be mentioned that, in the literature, other examples of disubstituted pyrenes by triazolyl groups are present, but the synthetic methodology is similar [65,66]. Applying the Sonogashira coupling reaction in the synthesis of disubstituted pyrenes containing directly substituted (hetero)aryl groups was described by Bo Song and co-workers [64]. The authors presented the synthetic route leading to 1,6-diethynylpyrene 60, which was obtained in a two-step reaction with a 44% yield. That compound was suitable for the Huisgen cycloaddition reaction, which allowed for the synthesizing of pyrene substituted by triazolyl groups 61 (Scheme 37). It should be mentioned that, in the literature, other examples of disubstituted pyrenes by triazolyl groups are present, but the synthetic methodology is similar [65,66].

Ullmann, Buchwald-Hartwig, Rosenmund-von Braun, and Substitution Reactions
Another important approach to the synthesis of disubstituted pyrenes is based on Ullmann C-N coupling reaction, described by Yoon Soo Han and co-workers, where 1,6-di(9H-carbazol-9-yl)pyrene 62 was obtained at the presence of Cu/K2CO3 in PhNO2, which resulted in a product with 27% yield (Scheme 38) [67].

Ullmann, Buchwald-Hartwig, Rosenmund-von Braun, and Substitution Reactions
Another important approach to the synthesis of disubstituted pyrenes is based on Ullmann C-N coupling reaction, described by Yoon Soo Han and co-workers, where 1,6-di(9H-carbazol-9-yl)pyrene 62 was obtained at the presence of Cu/K 2 CO 3 in PhNO 2 , which resulted in a product with 27% yield (Scheme 38) [67].

Ullmann, Buchwald-Hartwig, Rosenmund-von Braun, and Substitution Reactions
Another important approach to the synthesis of disubstituted pyrenes is based on Ullmann C-N coupling reaction, described by Yoon Soo Han and co-workers, where 1,6-di(9H-carbazol-9-yl)pyrene 62 was obtained at the presence of Cu/K2CO3 in PhNO2, which resulted in a product with 27% yield (Scheme 38) [67].
The same coupling reaction was also applied for the previously described product of mono Suzuki-Miyaura coupling reaction 50, which allowed the introduction of the diphenylamine moiety into the structure at 6-position with a 58% yield 64 (Scheme 40) [60]. The same coupling reaction was also applied for the previously described product of mono Suzuki-Miyaura coupling reaction 50, which allowed the introduction of the diphenylamine moiety into the structure at 6-position with a 58% yield 64 (Scheme 40) [60].
The same coupling reaction was also applied for the previously described product of mono Suzuki-Miyaura coupling reaction 50, which allowed the introduction of the diphenylamine moiety into the structure at 6-position with a 58% yield 64 (Scheme 40) [60]. 1,6-And 1,8-disubstituted pyrenes by 2-butyl-2H-1,2,3,4-tetrazol-5-yl groups 66 and 68 were synthesized starting from pure dibromo isomers in which, as the result of the Rosenmund-von Braun reaction using CuCN in NMP, bromine atoms were exchanged on cyano groups 65 and 67. The obtained intermediates were suitable for the cycloaddition reaction [3 + 2] using NaN 3 /NH 4 Cl in a DMF solution, followed by the alkylation with butyl bromide. This resulted in molecules 66 and 68 with 45% and 48% yields (Scheme 41) [68].

Reaction with a Mixture of 1,6-and 1,8-dibromo Isomers
Depending on target molecules and separation possibility of isomers, there is also another approach to the synthesis of 1,6-and 1,8-disubstituted pyrenes, which was presented by three research teams. Krzysztof Idzik and co-workers described the spectrum of pyrene derivatives containing furyl and thienyl units substituted at various positions of pyrene. In the case of 1,6-and 1,8-isomers, as a starting material, the mixture of 1,6-and 1,8-dibromopyrenes (authors described the isomers as 1,6-and 1,4-) was applied in the Stille-coupling reaction with 2-(tributylstannyl)thiophene or 2-(tributylstannyl)furan. This resulted in mixtures of isomers that were isolated using column chromatography, yielding compounds 70 (80%) and 71 (10%) in the case of thienyl units and 72 (70%) and 73 (10%) containing furyl groups (Scheme 43) [69,70]. It should be noted that the yields of reaction strongly depend on the applied bromination method of pyrene, and Scheme 41. Rosenmund-von Braun reaction followed by cycloaddition reaction [68].

Reaction with a Mixture of 1,6-and 1,8-dibromo Isomers
Depending on target molecules and separation possibility of isomers, there is also another approach to the synthesis of 1,6-and 1,8-disubstituted pyrenes, which was presented by three research teams. Krzysztof Idzik and co-workers described the spectrum of pyrene derivatives containing furyl and thienyl units substituted at various positions of pyrene. In the case of 1,6-and 1,8-isomers, as a starting material, the mixture of 1,6-and 1,8-dibromopyrenes (authors described the isomers as 1,6-and 1,4-) was applied in the Stille-coupling reaction with 2-(tributylstannyl)thiophene or 2-(tributylstannyl)furan. This resulted in mixtures of isomers that were isolated using column chromatography, yielding compounds 70 (80%) and 71 (10%) in the case of thienyl units and 72 (70%) and 73 (10%) containing furyl groups (Scheme 43) [69,70]. It should be noted that the yields of reaction strongly depend on the applied bromination method of pyrene, and

Reaction with a Mixture of 1,6-and 1,8-dibromo Isomers
Depending on target molecules and separation possibility of isomers, there is also another approach to the synthesis of 1,6-and 1,8-disubstituted pyrenes, which was presented by three research teams. Krzysztof Idzik and co-workers described the spectrum of pyrene derivatives containing furyl and thienyl units substituted at various positions of pyrene. In the case of 1,6-and 1,8-isomers, as a starting material, the mixture of 1,6-and 1,8-dibromopyrenes (authors described the isomers as 1,6-and 1,4-) was applied in the Stille-coupling reaction with 2-(tributylstannyl)thiophene or 2-(tributylstannyl)furan.
This resulted in mixtures of isomers that were isolated using column chromatography, yielding compounds 70 (80%) and 71 (10%) in the case of thienyl units and 72 (70%) and 73 (10%) containing furyl groups (Scheme 43) [69,70]. It should be noted that the yields of reaction strongly depend on the applied bromination method of pyrene, and the authors did not report the ratio of the starting material mixture.   They also reported another example where a mixture of the two dibromopyrenes reacted with 2-bromophenylboronic acid at conditions, which resulted in a mixture of diindenopyrenes, but there was no possibility to separate the isomers. Therefore, a two-step variant was applied, obtaining pure isomers 82 and 83 with a total reaction efficiency of 64% (Scheme 46), which were reacted further in the direction of diindenopyrenes [71].   They also reported another example where a mixture of the two dibromopyrenes reacted with 2-bromophenylboronic acid at conditions, which resulted in a mixture of diindenopyrenes, but there was no possibility to separate the isomers. Therefore, a two-step variant was applied, obtaining pure isomers 82 and 83 with a total reaction efficiency of 64% (Scheme 46), which were reacted further in the direction of diindenopyrenes [71]. Scheme 44. Suzuki-Miyaura coupling reaction with a mixture of dibromo isomers [6,9]. Lawrence T. Scott et al. also applied a mixture of 1,6-and 1,8-dibromopyrene (the ratio of the starting material mixture is unknown) in the Suzuki-Miyaura coupling reaction with 2-methoxyphenylboronic acid, and the obtained isomers 80 and 81 were separated by a simple treatment with acetone, resulting in the products with 58% (80) and 32% (81) yields (Scheme 45) [71].   They also reported another example where a mixture of the two dibromopyrenes reacted with 2-bromophenylboronic acid at conditions, which resulted in a mixture of diindenopyrenes, but there was no possibility to separate the isomers. Therefore, a two-step variant was applied, obtaining pure isomers 82 and 83 with a total reaction efficiency of 64% (Scheme 46), which were reacted further in the direction of diindenopyrenes [71]. They also reported another example where a mixture of the two dibromopyrenes reacted with 2-bromophenylboronic acid at conditions, which resulted in a mixture of diindenopyrenes, but there was no possibility to separate the isomers. Therefore, a two-step variant was applied, obtaining pure isomers 82 and 83 with a total reaction efficiency of 64% (Scheme 46), which were reacted further in the direction of diindenopyrenes [71].

Acetylpyrenes
Apart from 1,6-and 1,8-dibromopyrenes, the significant role as a starting material in the synthesis of 1,6-, 1,8-, and 1,3-disubstituted pyrenes by heteroaryl groups play acetylpyrenes due to the wide possibility of functionalization of an acetyl group [72]. Their synthesis is based on the acylation of pyrene using acetyl chloride (AcCl), what resulted in disubstituted and various isomers of acetylpyrenes (Scheme 47). Reaction conditions reported in the literature are based on AcCl with AlCl3 as a catalyst in carbon disulfide, which results in 1,8-diacetylpyrene 85 with the highest yields up to 46%, followed by 1,6isomer 84 and 1,3-diacetylpyrene 86. [73][74][75] Separation of the isomers can be achieved by crystallization or column chromatography (Table 3). Moreover, application of the ionic liquid (1methyl-3-ethylimidazolium chloride) in the acylation of pyrene was described by Martyn J. Earle et al., which resulted in a mixture of 1,6-and 1,8-isomer with total reaction efficiency of 55% [76].

Acetylpyrenes
Apart from 1,6-and 1,8-dibromopyrenes, the significant role as a starting material in the synthesis of 1,6-, 1,8-, and 1,3-disubstituted pyrenes by heteroaryl groups play acetylpyrenes due to the wide possibility of functionalization of an acetyl group [72]. Their synthesis is based on the acylation of pyrene using acetyl chloride (AcCl), what resulted in disubstituted and various isomers of acetylpyrenes (Scheme 47).

Acetylpyrenes
Apart from 1,6-and 1,8-dibromopyrenes, the significant role as a starting material in the synthesis of 1,6-, 1,8-, and 1,3-disubstituted pyrenes by heteroaryl groups play acetylpyrenes due to the wide possibility of functionalization of an acetyl group [72]. Their synthesis is based on the acylation of pyrene using acetyl chloride (AcCl), what resulted in disubstituted and various isomers of acetylpyrenes (Scheme 47). Reaction conditions reported in the literature are based on AcCl with AlCl3 as a catalyst in carbon disulfide, which results in 1,8-diacetylpyrene 85 with the highest yields up to 46%, followed by 1,6isomer 84 and 1,3-diacetylpyrene 86. [73][74][75] Separation of the isomers can be achieved by crystallization or column chromatography (Table 3). Moreover, application of the ionic liquid (1methyl-3-ethylimidazolium chloride) in the acylation of pyrene was described by Martyn J. Earle et al., which resulted in a mixture of 1,6-and 1,8-isomer with total reaction efficiency of 55% [76]. Reaction conditions reported in the literature are based on AcCl with AlCl 3 as a catalyst in carbon disulfide, which results in 1,8-diacetylpyrene 85 with the highest yields up to 46%, followed by 1,6-isomer 84 and 1,3-diacetylpyrene 86. [73][74][75] Separation of the isomers can be achieved by crystallization or column chromatography (Table 3). Moreover, application of the ionic liquid (1-methyl-3-ethylimidazolium chloride) in the acylation of pyrene was described by Martyn J. Earle et al., which resulted in a mixture of 1,6-and 1,8-isomer with total reaction efficiency of 55% [76].  In 2016, Mahesh Hariharan et al. described the way of synthesis of bisthiazolylpyrenes starting from the pure isomers of acetylpyrenes 84-86, which were then reacted with copper(II) bromide resulted in bromoacetylpyrene derivatives 92, 94, and 96. Intermediates were used in the Hantzsch condensation reaction between thioacetamide and appropriate bis(bromoacetyl)pyrene, which obtained target molecules 93, 95, and 97 with 64%, 68%, and 55% yields, respectively (Scheme 51) [78]. It should be noted that, as the result of all presented condensations reactions, isomers with substitution pattern 1,8 were obtained with the highest yields. Scheme 50. Friedländer reaction resulting in pyrenes with phenanthrolinyl units [74].

Condensation Reactions with Acetylpyrenes
In 2016, Mahesh Hariharan et al. described the way of synthesis of bisthiazolylpyrenes starting from the pure isomers of acetylpyrenes 84-86, which were then reacted with copper(II) bromide resulted in bromoacetylpyrene derivatives 92, 94, and 96. Intermediates were used in the Hantzsch condensation reaction between thioacetamide and appropriate bis(bromoacetyl)pyrene, which obtained target molecules 93, 95, and 97 with 64%, 68%, and 55% yields, respectively (Scheme 51) [78]. It should be noted that, as the result of all presented condensations reactions, isomers with substitution pattern 1,8 were obtained with the highest yields.

1,3-Disubstituted Pyrene
The most challenging of disubstituted pyrenes are the derivatives with the 1,3-substitution pattern, as presented earlier. Apart from their synthesis starting from 1,3-diacetylpyrene, which allows for the introduction of a limited group of substituents into the pyrene structure at positions 1 and 3, another approach is presented in the literature. Takehiko Yamato et al. reported 1,3diphenylpyrene 101, which was obtained in a multistep procedure [79]. As the first step, the introduction of the protecting group was achieved by the alkylation of pyrene at the 2-position by tert-butyl chloride, resulting in molecule 98 with a 71% yield [79]. The intermediate 98 was brominated by benzyltrimethylammonium tribromide (BTMABr3), which led to the synthesis of 1,3dibromo-7-tert-butylpyrene 99 with a 76% yield (Scheme 52). Compound 99 was used in the Suzuki-Miyaura coupling reaction with phenylboronic acid and molecule 100 containing phenyl groups at positions 1 and 3, and a protecting group at 7-position was obtained. Removing the protecting tert-butyl was conducted by using Nafion-H as a catalyst, which resulted in compound 101 with an 80% yield (Scheme 53) [80].

1,3-Disubstituted Pyrene
The most challenging of disubstituted pyrenes are the derivatives with the 1,3-substitution pattern, as presented earlier. Apart from their synthesis starting from 1,3-diacetylpyrene, which allows for the introduction of a limited group of substituents into the pyrene structure at positions 1 and 3, another approach is presented in the literature. Takehiko Yamato et al. reported 1,3-diphenylpyrene 101, which was obtained in a multistep procedure [79]. As the first step, the introduction of the protecting group was achieved by the alkylation of pyrene at the 2-position by tert-butyl chloride, resulting in molecule 98 with a 71% yield [79]. The intermediate 98 was brominated by benzyltrimethylammonium tribromide (BTMABr 3 ), which led to the synthesis of 1,3-dibromo-7-tert-butylpyrene 99 with a 76% yield (Scheme 52).

1,3-Disubstituted Pyrene
The most challenging of disubstituted pyrenes are the derivatives with the 1,3-substitution pattern, as presented earlier. Apart from their synthesis starting from 1,3-diacetylpyrene, which allows for the introduction of a limited group of substituents into the pyrene structure at positions 1 and 3, another approach is presented in the literature. Takehiko Yamato et al. reported 1,3diphenylpyrene 101, which was obtained in a multistep procedure [79]. As the first step, the introduction of the protecting group was achieved by the alkylation of pyrene at the 2-position by tert-butyl chloride, resulting in molecule 98 with a 71% yield [79]. The intermediate 98 was brominated by benzyltrimethylammonium tribromide (BTMABr3), which led to the synthesis of 1,3dibromo-7-tert-butylpyrene 99 with a 76% yield (Scheme 52). Compound 99 was used in the Suzuki-Miyaura coupling reaction with phenylboronic acid and molecule 100 containing phenyl groups at positions 1 and 3, and a protecting group at 7-position was obtained. Removing the protecting tert-butyl was conducted by using Nafion-H as a catalyst, which resulted in compound 101 with an 80% yield (Scheme 53) [80]. Compound 99 was used in the Suzuki-Miyaura coupling reaction with phenylboronic acid and molecule 100 containing phenyl groups at positions 1 and 3, and a protecting group at 7-position was obtained. Removing the protecting tert-butyl was conducted by using Nafion-H as a catalyst, which resulted in compound 101 with an 80% yield (Scheme 53) [80].

Synthesis of 1,3,6,8-tetrasubstituted Starting from Disubstituted Pyrenes
In many cases, disubstituted pyrenes by (hetero)aryl groups act as substrates in the subsequent reactions: functionalization of already introduced substituents or the introduction of other groups into the pyrene structure at unoccupied positions, especially at the non-K region, which is possible by the introduction of bromine atoms. Brominating agent bromine solution in DMF or CHCl3 was used, which resulted in products with yields above 95% (Scheme 54-55) [6,9,44].

Synthesis of 1,3,6,8-tetrasubstituted Starting from Disubstituted Pyrenes
In many cases, disubstituted pyrenes by (hetero)aryl groups act as substrates in the subsequent reactions: functionalization of already introduced substituents or the introduction of other groups into the pyrene structure at unoccupied positions, especially at the non-K region, which is possible by the introduction of bromine atoms. Brominating agent bromine solution in DMF or CHCl 3 was used, which resulted in products with yields above 95% (Schemes 54 and 55) [6,9,44].

Synthesis of 1,3,6,8-tetrasubstituted Starting from Disubstituted Pyrenes
In many cases, disubstituted pyrenes by (hetero)aryl groups act as substrates in the subsequent reactions: functionalization of already introduced substituents or the introduction of other groups into the pyrene structure at unoccupied positions, especially at the non-K region, which is possible by the introduction of bromine atoms. Brominating agent bromine solution in DMF or CHCl3 was used, which resulted in products with yields above 95% (Scheme 54-55) [6,9,44].

Summary
The review of structures of 1,3-, 1,6-, and 1,8-disubstituted pyrenes by (hetero)aryl groups and the methods for their synthesis revealed that the number of 1,6-isomer derivatives is the highest and compounds are preferably obtained using the Suzuki-Miyaura coupling reaction. The main reason for taking interesting in those compounds is connected with their optical and photophysical properties, which make them potential materials for broadly defined organic electronics. The wide possibility of obtaining of 1,6-and 1,8-dibromopyrene, unlike 1,3-dibromopyrene, showed that, in the case of 1,3-isomer, indirect methods must be applied. Moreover, acylation of pyrene allows 1,3-, 1,6-, and 1,8-isomers to be obtained, which can be successfully used in condensation reactions that

Summary
The review of structures of 1,3-, 1,6-, and 1,8-disubstituted pyrenes by (hetero)aryl groups and the methods for their synthesis revealed that the number of 1,6-isomer derivatives is the highest and compounds are preferably obtained using the Suzuki-Miyaura coupling reaction. The main reason for taking interesting in those compounds is connected with their optical and photophysical properties, which make them potential materials for broadly defined organic electronics. The wide possibility of obtaining of 1,6-and 1,8-dibromopyrene, unlike 1,3-dibromopyrene, showed that, in the case of 1,3-isomer, indirect methods must be applied. Moreover, acylation of pyrene allows 1,3-, 1,6-, and 1,8-isomers to be obtained, which can be successfully used in condensation reactions that result in products with high yields. I believe that, as the results of the presented systematization and described diversity in the area of disubstituted pyrenes at the non-K region, the expected direction in pyrene chemistry will be followed.