Synthesis of partially and fully fused polyaromatics by annulative chlorophenylene dimerization

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Science  26 Jan 2018:
Vol. 359, Issue 6374, pp. 435-439
DOI: 10.1126/science.aap9801

How to get two bonds for the price of one

For more than a century, we have known how to couple aryl chlorides at the sites of their C-Cl bonds to form a single C-C bond. Koga et al. found that palladium catalysis can instead activate these C-Cl bonds to attack nearby aromatic C-H bonds in a terphenyl molecular framework. The reaction thereby produces a new ring, fused to the original rings on either side. Polycyclic compounds of this sort are of particular interest in optoelectronics research because of their expansive electron delocalization.

Science, this issue p. 435


Since the discovery by Ullmann and Bielecki in 1901, reductive dimerization (or homocoupling) of aryl halides has been extensively exploited for the generation of a range of biaryl-based functional molecules. In contrast to the single-point connection in these products, edge-sharing fused aromatic systems have not generally been accessible from simple aryl halides via annulation cascades. Here we report a single-step synthesis of fused aromatics with a triphenylene core by the palladium-catalyzed annulative dimerization of structurally and functionally diverse chlorophenylenes through double carbon-hydrogen bond activation. The partially fused polyaromatics can be transformed into fully fused, small graphene nanoribbons, which are otherwise difficult to synthesize. This simple, yet powerful, method allows access to functional π-systems of interest in optoelectronics research.

The reductive dimerization (or homocoupling) of aryl halides (1) has been extensively exploited in organic synthesis since Ullmann and Bielecki’s discovery of the copper-mediated dimerization of aryl halides in 1901 (2) (Fig. 1A). This reaction has proved to be particularly useful in the synthesis of biaryl-based functional molecules, including pharmaceuticals, biologically active natural products, optoelectronic π-conjugated materials, and polymers. Although this textbook reaction is a powerful technique for the single-point connection of two aromatic nuclei, methods to access fused aromatic systems from simple aryl halides, via annulation cascades, have not been developed (Fig. 1A). Such fused polycyclic aromatics represent an emerging class of π-conjugated molecules in optoelectronic devices, nanographene materials (3), ultrashort carbon nanotubes (4), and carbon nanobelts (5). Their optoelectronic properties are susceptible to structural perturbations based on shape, width, edge topology, and degree of π-extension. Thus, a method to synthesize fused aromatics in a bottom-up fashion with atom-by-atom precision is in high demand (37). In particular, methods that involve C–H functionalization (8, 9), a direct molecular activation-transformation technology, are attractive not only to streamline overall synthesis but also to unlock opportunities for markedly different reactivity and selectivity. On the basis of our single-step π-extension strategy for making new nanocarbon molecules by C–H functionalization (10, 11), we envisioned that ortho-C–H bonds of aryl halides might be activated for annulative dimerization processes to access π-extended, fused polyaromatic systems (Fig. 1A).

Fig. 1 Potential of annulative dimerization of aryl halides.

(A) Classical reductive dimerization and annulative dimerization. (B) Pd-catalyzed annulative dimerization of chlorophenylenes to give triphenylene-based fused aromatics. (C) Optimized reaction conditions: 1a (1.0 equivalent), PdCl2 (5.0 mol %), PBu(Ad)2 (10 mol %), Cs2CO3 (3.0 equivalents), CPME, 140°C, 18 hours. (D) Effect of phosphine ligands. Conditions: 1a (1.0 equivalent), PdCl2 (5.0 mol %), ligand (10 mol %), Cs2CO3 (3.0 equivalents), CPME, 140°C, 18 hours. 1H NMR yields of 2a are given in parentheses. Red bonds indicates those that are newly formed.

Here we report a single-step synthesis of triphenylene-cored, fused aromatics by the palladium-catalyzed annulative dimerization of structurally and functionally diverse chlorophenylenes (12, 13) through double C–H activation (Fig. 1B). The overall reaction is redox-neutral, such that stoichiometric reductant is not required. Chlorinated aromatic reagents are readily available. This simple, yet powerful, dimerization allows for the fusion of two functional aromatic nuclei to directly access triphenylene-cored π-systems that are known as privileged structures for materials in organic light-emitting diodes (OLEDs) (1417). Moreover, the thus-generated partially fused aromatics can be transformed into fully fused, small graphene nanoribbons, which are otherwise difficult to synthesize.

We began our campaign by establishing the conditions for the annulative dimerization reaction using 2′-chloro-1, 1′:4′, 1″-terphenyl (1a) as a representative chlorinated oligophenylene. Through extensive screening of various catalysts and additives, we identified the optimized reaction conditions: Treatment of 1a (1.0 equivalent) with PdCl2 [5.0 mole % (mol %)], PBu(Ad)2 (10 mol %; Bu, n-butyl; Ad, 1-adamantyl), and cesium carbonate (3.0 equivalents) in cyclopentyl methyl ether (CPME) at 140°C for 18 hours afforded the annulative dimerization product 2a in 81% isolated yield (Fig. 1C). The structure of 2a was unambiguously confirmed by x-ray crystallographic analysis. The ligand had a critical effect on the reaction efficiency; representative results are shown in Fig. 1D. The use of less bulky PBu3 hindered the reaction. Moderately large trialkylphosphines PCy3 (Cy, cyclohexyl) and PBu(Ad)2 afforded the best results (77 and 82%), whereas much bulkier PtBu3 (tBu, tert-butyl) did not facilitate the dimerization. Other phosphine ligands P(o-tol)3 (o-tol, o-CH3C6H4) and 1,2-bis(dicyclohexylphosphino)ethane, as well as N-heterocyclic carbene ligands, were not effective for the reaction.

Although the exact mechanism of the annulative dimerization remains unclear, our current assumption is shown in Fig. 2. An in situ–generated, phosphine-bound Pd(0) species Pd0L [L, PBu(Ad)2] undergoes the first oxidative addition with chloroterphenyl 1a to give arylpalladium A. The resulting arylpalladium A can abstract three hydrogen atoms via path 1, intramolecular HA (red); path 2, intramolecular HB (blue); or path 3, intermolecular HC (green). Path 1 initiates from intramolecular ortho-C–H activation (18) from A to give Pd-aryne B (19). Oxidative addition of 1a to B provides C, which undergoes an insertion (carbopalladation) across the aryne moiety to give arylpalladium D. Subsequent intramolecular C–H palladation affords seven-membered palladacycle E, which then undergoes reductive elimination to provide triphenylene product 2a and Pd0L, completing the catalytic cycle. As an alternative to the Pd-aryne pathway (path 1), the Pd(IV) pathway (path 2) might also be possible (20). For example, intramolecular C–H activation of A at the baylike region affords palladacycle intermediate F. Subsequent oxidative addition of 1a generates Pd(IV) intermediate G, which then undergoes biaryl-forming reductive elimination to yield arylpalladium H. Intramolecular C–H activation affords I, which finally gives 2a and Pd0L. Path 3 involves intermolecular C–H activation of A with 1a, whereby the C–H bond ortho to the chlorine atom is activated, to give intermediate J, which then provides K. Subsequent intramolecular C–H arylation of K affords 2a through intermediates D and E.

Fig. 2 Possible reaction pathways.

Three pathways are shown: path 1, ortho C–H activation pathway; path 2, bay C–H activation pathway; and path 3, intermolecular C–H activation pathway. Ph, phenyl; L, PBu(Ad)2; X, Cl or CO3Cs.

With the optimal conditions for the annulative dimerization in hand, the scope of the reaction was investigated with a range of structurally and functionally diverse chlorophenylenes (Fig. 3A). Terphenyl 1b with a tBu group was converted into the corresponding triphenylene derivative 2b in 77% isolated yield. Terphenyls with an electron-donating methoxy, trifluoromethoxy, methylsulfanyl, or electron-withdrawing trifluoromethyl group (1c to 1f) were smoothly converted into 2c to 2f in good to high yields (85, 68, 49, and 64%, respectively). The methylsulfanyl group can be transformed through metal-catalyzed cross-coupling reactions as a halogen equivalent. Silyl groups, which can be used for further derivatizations, were also tolerated, and 2g was obtained in 66% yield. In the reaction of 1h, the methoxycarbonyl group remained intact to give 2h. A small amount of isomer 2h′ was also generated, presumably because the ester group increased the acidity of the C–H bond on the arene to induce an unwanted palladium migration through the palladacycle intermediate (21). The reaction of 1i afforded carbazole-containing triphenylene 2i that could have potential as a hole-transporting material. m-Methyl– or m-phenyl–substituted 1j and 1k reacted smoothly to give 2j and 2k in 85 and 58% yields, respectively. Chlorobenzene derivatives with two naphthalene rings (1l and 1m) dimerized to give fused π-extended systems 2l and 2m in 73 and 91% yields with virtually complete regioselectivity. No further dehydrocyclization was observed. Benzothiophene-substituted derivative 1n also reacted to give thiophene-benzene fused system 2n. Chlorinated thiophene derivative 1o also underwent annulative dimerization to give 2o in 33% yield.

Fig. 3 Annulative dimerization with various substrates.

Optimized reaction conditions: 1 (1.0 equivalent), PdCl2 (5.0 mol %), PBu(Ad)2 (10 mol %), Cs2CO3 (3.0 equivalents), CPME, 140°C, 18 hours. (A) Scope to examine functional group compatibility and structural diversity. *Ratio of 2h to 2hʹ is 3:1. For the structure of 2hʹ, see supplementary materials. †CsF (3.0 equivalents) was used instead of Cs2CO3. Me, methyl. (B) Reaction of 1p. ‡Ratio of 2p to 2pʹ is 3:1. (C) No chloride or palladium migration occur. L, PBu(Ad)2; Ar, aromatic; X, Cl or CO3Cs.

By applying various chloroarene substrates to the present annulative dimerization, mechanistic insights were also obtained. An overview of possible reaction pathways and the mechanistic experiments are provided in the supplementary materials. For example, chloroterphenyl 1p is useful as a mechanistic probe (Fig. 3B). The reaction of 1p resulted in the formation of a mixture of 2p and 2p′, structures of which were confirmed by x-ray crystallographic analysis. This shows that either path 1 or 2 was dominant and that the mixture of 2p and 2p′ was generated through Pd-aryne intermediate M or palladacycle intermediate F (Fig. 3B). Intermediate M or F then reacted with 1p to give two regioisomers. On the other hand, if path 3 had been dominant, the reaction would have resulted in the exclusive formation of 2p via intermediate N. Importantly, this discussion is based on the hypothesis that no chloride or palladium migration occurs in the substrate and/or intermediates (Fig. 3C). From extensive experiments, we confirmed that such chloride or palladium migration is not taking place under the present reaction conditions (figs. S17 to S21). Taken together, we conclude that the intermolecular C–H activation pathway (path 3) is unlikely. Because both possible pathways, paths 1 and 2, involve previously unappreciated elementary reactions [the formation of Pd-aryne via ortho-C–H activation of arylpalladium or the oxidative addition of an aryl chloride to a palladacycle (22)], the mechanism of the present reaction is of great interest in its own right.

The construction of polycyclic aromatics has garnered considerable attention owing to their applicability in a range of functional materials. It is particularly important to synthesize these materials in a controlled fashion, because their structure profoundly affects their properties. In this study, all triphenylene-cored, π-extended compounds 2 display blue fluorescence with reasonably sharp spectral widths. The photophysical properties (ultraviolet through visible absorption spectra, fluorescence spectra, and fluorescence quantum yields) of 2 are provided in figs. S30 to S48. Coupled with their nonplanar molecular structures, these new molecules should have considerable potential as materials for OLEDs (1417). For example, as reported by Adachi, triphenylene-based molecules with bipyridine substituents are high–molecular orientation electron-transport materials (15, 16) that have become one of the standard materials for OLEDs (17).

In addition to their potential use as optoelectronic materials, the annulation products also serve as partially fused polyaromatics and may be useful soluble precursors for the synthesis of fully fused, graphene nanoribbon substructures via Scholl-type dehydrocyclizations (23) (Fig. 4A). As a proof-of-concept, we used the annulative dimerization-dehydrocyclization sequence for the synthesis of fully fused nanographenes (Fig. 4B). Triphenylene 2a was treated with FeCl3 in CH2Cl2 at 0°C (standard conditions for the Scholl reaction), and 3 was obtained in 77% yield (62% two-step yield from 1a). The clean, high-yielding formation of 3 without any optimization was quite surprising. It is well known that unwanted side reactions such as arene rearrangement (24) and aromatic chlorination often take place with polyaromatic compounds (23) in Scholl chemistry. For example, when polyphenylene 4, which can be prepared by the nickel-catalyzed reductive dimerization of 1a (25), was subjected to the standard Scholl conditions (FeCl3, CH2Cl2, 0°C), the fully fused product 3 was not obtained; instead, a complex mixture of various unidentified products (most likely arene rearrangement products) was obtained. Thus, there is a clear advantage of the present reaction, accessing partially fused structures (triphenylene substructures in this case), to ensure that subsequent dehydrocyclization occurs successfully. This ring-fusing sequence, enabled by the annulative dimerization reaction, facilitates the synthesis of privileged fused π-conjugated systems, which are otherwise difficult to synthesize.

Fig. 4 Access to graphene nanoribbon substructures.

(A) Rapid synthesis of partially and fully fused polyaromatics enabled by annulative dimerization of chlorophenylenes. (B) Advantage of annulative dimerization over classical reductive dimerization in the synthesis of fully fused phenylene 3. THF, tetrahydrofuran; Et, ethyl. (C) Synthesis of graphene nanoribbon substructure 5. Reaction conditions: *1,4-dibromo-2-chlorobenzene (1.0 equivalent), 4-biphenylboronic acid (2.4 equivalents), PdCl2(PPh3)2 (2.0 mol %), K2CO3 (5.0 equivalents), toluene/H2O/ethanol, 80°C, 18 hours, 92%. †PdCl2 (5.0 mol %), PBu(Ad)2 (10 mol %), Cs2CO3 (3.0 equivalents), CPME (1.0 M of 1q), 140°C, 18 hours, 64%. ‡2q (0.010 mmol), FeCl3 (0.47 mmol), CH2Cl2 (2.0 ml), room temperature, 42 hours, 72%.

To further demonstrate the utility of the present strategy, the rapid and convergent synthesis of an armchair-edged graphene nanoribbon segment (3, 2631) was carried out (Fig. 4C). 1,4-Dibromo-2-chlorobenzene was treated with p-biphenylylboronic acid in the presence of a palladium catalyst (Suzuki-Miyaura cross-coupling) to give chloropentaphenyl 1q (92% yield). The palladium-catalyzed annulative dimerization of 1q afforded partially fused product 2q (64% yield). Finally, the Scholl reaction of 2q gave small graphene nanoribbon segment C60H26 (5) in 72% yield. Notably, this 60-carbon nanoribbon 5 was obtained from 1,4-dibromo-2-chlorobenzene in three steps in 42% overall yield. The Raman and Fourier transform infrared spectra of small nanoribbon 5 were quite similar to the calculated spectra, supporting the formation of the expected nanoribbon structure (see figs. S7, S12, and S13 for details). This represents a very rare example of access to fully fused planar nanographenes without any solubilizing substituents under solution-phase conditions (3234). Overall, the annulative dimerization reaction sequence reported here should drastically alter the execution of partially and fully fused polyaromatics, as chlorine and ortho hydrogen atoms on aromatic nuclei can now be considered ring-fusing handles.

Supplementary Materials

Materials and Methods

Figs. S1 to S188

Table S1

References (3547)

References and Notes

Acknowledgments: This work was supported by JST ERATO grant number JPMJER1302 (K.I.) and JSPS KAKENHI grant numbers JP15K17821 and JP17H04868 (K.M.). We are grateful to Y. Segawa, H. Ito, and T. Yoshidomi for assistance with x-ray crystal structure analysis and fruitful discussions. We acknowledge Y. Miyauchi and A. Takakura for assistance with Raman measurements, H. Sakamoto and N. Ozaki for assistance with Fourier transform infrared measurements, and K. Kuwata and K. Ito for assistance with high-resolution mass spectrometry measurements. ITbM is supported by the World Premier International Research Center Initiative (WPI). Crystallographic data for compounds 2a, 2p, and 2p′ are available free of charge from the Cambridge Crystallographic Data Centre under CCDC identifiers 1518668, 1518669, and 1518670, respectively ( All authors are inventors on a patent application (PCT/JP2017/020703) submitted by Nagoya University that covers the synthetic methods and molecules included in this paper.
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