Diversity-oriented synthesis of nanographenes enabled by dearomative annulative π-extension

Nanographenes and polycyclic aromatic hydrocarbons (PAHs) are among the most important classes of compounds, with potential applications in nearly all areas of science and technology. While the theoretically possible number of nanographene structures is extraordinary, most of these molecules remain synthetically out of reach due to a lack of programmable and diversity-oriented synthetic methods, and their potentially huge structure-property diversity has not been fully exploited. Herein we report a diversity-oriented, growth-from-template synthesis of nanographenes enabled by iterative annulative π-extension (APEX) reactions from small PAH starting materials. The developed dearomative annulative π-extension (DAPEX) reaction enables π-elongation at the less-reactive M-regions of PAHs, and is successfully combined with complementary APEX reactions that occur at K- and bay-regions to access a variety of previously untapped nanographenes.

N anographenes and polycyclic aromatic hydrocarbons (PAHs) are among the most important classes of compounds, with potential applications in nearly all areas of materials science, and particular promise in organic electronics, biology, and space science [1][2][3][4] . Nanographenes and PAHs are structurally simple assemblies of benzene-based hexagons and one can imaginarily build up a range of structures with ease 5 . While seemingly simple, the structural diversity of nanographenes and PAHs is extraordinary (Fig. 1a), and the enumeration of these molecules (also known as Kekuléan fusenes) using graph theory has been of central interest in mathematical chemistry 6 . The number of possible structures of nanographenes and PAHs (N) from n hexagons rapidly becomes extremely high even in relatively small systems (N = 52 when n = 6; N = 195 when n = 7; N = 16,025 when n = 10) and increases roughly fivefold for every additional hexagon (N > 10 15 when n = 25). Since the key characteristics of nanographenes and PAHs-such as their photophysical, electronic, magnetic, and self-assembling properties-are determined by their structures [1][2][3][4] , a comprehensive evaluation of nanographenes is required to fully understand the relationship between their molecular structures and properties. However, to the best of our knowledge, most of the theoretically possible structures remain unsynthesized and unexplored in experimental science in reality (Fig. 1a). Moreover, while nature provides a tremendous variety of PAHs as components of fuel, coal, and tar, as well as side-products in combustion, interstellar dust, and meteorites 4,7 , only an extremely limited number of pure PAHs can be reliably accessed from these natural sources due to challenges in isolation.
The only logical way to access and utilize a greater diversity of structurally pure PAHs and nanographenes is to draw inspiration from organic synthesis, where a target molecular entity is built up from a template (seed) molecule with structural precision. While decades of research into the synthetic chemistry of PAHs has uncovered a number of exciting properties and applications [1][2][3][4][7][8][9][10][11][12][13] , thereby contributing significantly to the emergence of nanographene science, the synthetic bottleneck remains considerable. Owing to the lack of predictable and diversity-oriented synthetic methods for their synthesis 14 , the huge structure-property diversity of nanographenes has not been fully exploited. One intuitive, programmable, and potentially diversity-oriented synthetic strategy would be the "growth-fromtemplate" approach, in which nanographenes are built up from small PAH templates by regioselective, template-elongating annulative π-extension (APEX) reactions (Fig. 1b) 15 . The regioselective and direct construction of fused aromatic rings on a peripheral region of an unfunctionalized aromatic template would result in the formation of another, larger aromatic template, and repeating this protocol would grant access to diverse nanographene structures. This APEX methodology is very different from typical nanographene syntheses, which consist of multiple synthetic steps including prefunctionalization of aromatics, component assembly into polyarylene precursors, and dehydrocyclization [8][9][10][11][12][13] . While challenges exist in obtaining APEX regioselectivity among the structurally and electronically similar C-H bonds and PAH regions found in unfunctionalized aromatic templates, this diversity-oriented strategy enables access to a range of previously untapped nanographene structures in an intuitive fashion, thereby revolutionizing nanographene synthesis.
To this end, we have established several palladium-catalyzed APEX reactions that occur at the K-region (convex armchair edge) of PAHs (Fig. 1b, K-APEX), realizing the synthesis of various nanographenes 16,17 . Clar, Scott, and others have achieved Diels-Alder-type APEX reactions at the bay-region (concave armchair edge) of PAHs (Fig. 1b, bay-APEX) [18][19][20][21] . To realize a diversity-oriented nanographene synthesis, APEX reactions that occur at other peripheral regions such as the terminal acene-like M-region are essential (Fig. 1b). M-region-selective APEX (M-APEX) is particularly challenging because the M-region is much less reactive compared to the "olefinic" K-region and "diene-like" bay-region-indeed, M-region (C2 and C3)-selective functionalizations of phenanthrene have been scarcely reported 22,23 .
We have previously developed several dearomative functionalizations by exploiting the ability of 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) as an arenophile, which can participate in photo-induced [4 + 2] cycloaddition with aromatic compounds [24][25][26] . During the study, we have discovered that the [4 + 2] cycloaddition of polyarenes with MTAD preferentially occurs on a terminal acene-like structure, likely to minimize steric repulsion, and the reaction furnishes an activated olefin moiety on the M-region of the PAH starting materials (Fig. 1c). Here, we report the long-sought-after, broadly applicable M-APEX reaction with a concept of "dearomative APEX" (DAPEX), involving the MTAD-mediated dearomative activation of an aromatic ring, annulation, and finally rearomatization (Fig. 1c). The diversity-oriented synthesis of nanographenes by combining K-, M-and bay-APEX reactions is also demonstrated.
The power of this DAPEX strategy becomes most apparent when strategically combining the present M-APEX with previously reported K-and bay-APEX reactions (Fig. 5). Iterative APEX reactions starting from phenanthrene are shown in Fig. 5a. M-APEX reaction of phenanthrene (1h) gave 5ha through rearomatization of the intermediate 4ha, as described in Fig. 2b. Conversely, palladium-catalyzed K-APEX reaction 17 of phenanthrene 8 with diiodobiaryl 1l successfully gave the corresponding π-extended PAH 9. Further APEX reactions at the remaining peripheral regions of 5ha and 9 are possible. For example, nanographene 10 was obtained by the K-APEX reaction of 5ha with diiodobiphenyl 20, while M-APEX of 9 gave nanographene 11 (see Supplementary Fig. 5 for X-ray crystal structure). Nanographene 11 can also be obtained directly from phenanthrene 8 by employing the pre-π-extended diiodobiaryl 5la as the π-extending agent for K-APEX. In addition to newly formed PAHs, APEX intermediates such as 4ha can also be employed as templates for further π-extension. Indeed, dearomatization and annulative diarylation of 4ha gave the corresponding tetraarylated product 6ha (see section 1.9 of Supplementary Information and Supplementary Fig. 6). Rearomatization with pchloranil proceeded to remove both of the urazole moieties and Step 1: 61% (with 3e ) Step 2: 90% O Step 1: 51% (with 3f ) Step 2: 66%

M-APEX
(v) with 3a Step 1: 42% Step 2: 39% Fig. 5 Diversity-oriented nanographene synthesis by growth-from-template method utilizing region-selective APEX reactions. a Nanographene synthesis from phenanthrene. b Nanographene synthesis from chrysene. c Nanographene synthesis from naphthalene. d Nanographene synthesis from perylene. Reaction conditions. NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24261-y ARTICLE afford the double M-APEX product 12. APEX reaction at the remaining K-region of 12 also proceeded to give nanographene 13 (see Supplementary Fig. 7 for X-ray crystal structure). It should be noted that for the APEX reactions of less-soluble compounds such as 12, a mechanochemical reaction setup with ball-milling 32 is advantageous (see section 1.12 of Supplementary  Information).
We further verified the utility of DAPEX strategy in the diversity-oriented synthesis of nanographenes. We previously clarified that the K-APEX reaction of chrysene (1k) with 2,2′diiodobiphenyl (20) gives the highly fused nanographene 14 in one step 17 , while the present M-APEX reaction of 1k with 3a gave the elongated product 5ka (Fig. 5b). The π-extended chrysene 5ka also worked as a new template for late-stage K-APEX, successfully affording nanographene 15 in 42% yield (see Supplementary  Fig. 8 for X-ray crystal structure). Another nanographene 16 could be synthesized starting from naphthalene (1g) through the sequence of M-APEX and K-APEX (Fig. 5c). The M-APEX of 1g with 2-(1-naphthyl)-phenyl magnesium bromide (3e′) gave the πextended PAH 5ge, bearing a newly-formed K-region. K-APEX reaction on this K-region also proceeded successfully to afford the nanographene 16 (see Supplementary Fig. 9 for X-ray crystal structure). As another related example for growth-from-template synthesis, we conducted the bay-APEX reaction of perylene with π-extending agent 22 to form naphthoperylele 18 21 , which was then subjected to K-APEX to access nanographene 19 (Fig. 5d).
In conclusion, we have established a concept of DAPEX that involves the dearomative activation of polyaromatic templates, annulative diarylation, and rearomatization, and realized a formal APEX reaction at the less-reactive M-region of aromatic templates. In addition, an intuitive, diversity-oriented synthesis of nanographenes has been achieved by combining the developed DAPEX and previous APEX reactions of PAHs. As many properties of nanographenes are not easily predicted, this powerful strategy capable of generating vast structural diversity in a programmable fashion will allow for an increased understanding of nanographene structure-property relationships. This will in turn aid in the discovery of hitherto unknown functional molecules and new guiding principles for the future rational property-driven design of nanographenes. The present study speaks well for the potential of regiodivergent PAH functionalization in the creation of nanographene libraries to confront the most significant challenges in materials science.

See Supplementary Information for detailed methods and characterization data.
The typical procedure for dearomatization of polyaromatics 1 followed by annulative diarylation. To a glass tube containing a magnetic stirring bar were added MTAD (0.10 mmol, 1.0 equiv) and polyaromatics 1 (0.20-1.0 mmol, 2.0-10 equiv). The tube was sealed with a septum, filled with N 2 gas, and then methyl acetate (20 mL) was added at ambient temperature. The contents were sonicated to dissolve solids as much as possible and then cooled to 0°C. The resulting pink solution was stirred under irradiation with LED lights at 0°C until the solution became colorless or brown (approx. for 2 h). After turning off the lights, the mixture was transferred to a 50 mL two-necked round-bottomed flask, and the volatile was removed in vacuo at 0°C. Then, the flask was filled with N 2 gas, and THF (2.5 mL) was added to dissolve the residue (solution A).
To another glass tube containing a magnetic stirring bar was added dppbz (0.01 mmol, 10 mol%). The tube was sealed with a septum and filled with N 2 gas. Then THF (1.0 mL), 1.9 M ZnCl 2 solution in 2-methyltetrahydrofuran (0.30 mmol, 3.0 equiv) and THF solution of 3a (0.30 mmol, 3.0 equiv) were added in this order at ambient temperature. Another portion of 1.9 M ZnCl 2 solution in 2methyltetrahydrofuran (0.30 mmol, 3.0 equiv) was added and then white precipitation was formed. This mixture was stirred at ambient temperature for 30 min and then cooled to 0°C. At this temperature, 0.20 M Fe(acac) 3 solution in THF (0.01 mmol, 10 mol%) was added, and the resulting mixture was stirred for 5 min. Then, 1,2-dichloroisobutane (0.15 mmol, 1.5 equiv) and solution A were added to this tube, and the mixture was stirred at ambient temperature for 2 h. The mixture was quenched with 1 M HCl aq. (approx. 10 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried with Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by PTLC to yield diarylated product 4.
The typical procedure for rearomatization of diarylated compound 4. To a screw-capped tube containing a magnetic stirring bar were added diarylated compound 4 (1.0 equiv) and p-chloranil (3.0 equiv). Then, 1,1,2,2-tetrachloroethane was added to this tube to prepare a 0.1 M solution of 4 under air. The tube was sealed with a cap, and the resulting mixture was stirred at 150°C for 36 h. Then, the reaction mixture was cooled to ambient temperature and diluted with chloroform (approx. 3 mL). To this mixture, hydrazine monohydrate (5.0 equiv) was added and the resulting mixture was stirred at ambient temperature for 15 min to quench the remaining p-chloranil. The mixture was washed with 1 M NaOH aq. (approx. 10 mL) and extracted with chloroform (3 × 30 mL). The combined organic layers were dried with Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to yield π-extended product 5.