Synthetic Applications of Oxidative Aromatic Coupling—From Biphenols to Nanographenes

Abstract Oxidative aromatic coupling occupies a fundamental place in the modern chemistry of aromatic compounds. It is a method of choice for the assembly of large and bewildering architectures. Considerable effort was also devoted to applications of the Scholl reaction for the synthesis of chiral biphenols and natural products. The ability to form biaryl linkages without any prefunctionalization provides an efficient pathway to many complex structures. Although the chemistry of this process is only now becoming fully understood, this reaction continues to both fascinate and challenge researchers. This is especially true for heterocoupling, that is, oxidative aromatic coupling with the chemoselective formation of a C−C bond between two different arenes. Analysis of the progress achieved in this field since 2013 reveals that many groups have contributed by pushing the boundary of structural possibilities, expanding into surface‐assisted (cyclo)dehydrogenation, and developing new reagents.


Introduction
Oxidative aromatic coupling and the Scholl reaction, both discovered more than 100 years ago, [1][2][3] have not lost any attraction to organic chemists in the last decade,d espite the appearance of many modern CÀHa ctivation procedures. These reactions are often the methods of choice for the synthesis of large p-extended scaffolds as well as smaller benzenoid or heteroaromatic compounds possessing biaryl linkages (Scheme 1). TheS choll reaction is undoubtedly the most useful for the construction of nanographenes [4,5] and their heterocyclic analogues. [6] Indeed, in some cases,m ore than 100 CÀCbonds are formed in one synthetic operation to furnish truly amazing polycyclic aromatic hydrocarbons from suitable precursors.T here is no other reaction that can duplicate this result for ad iscrete molecule (i.e.n ot ap olymer). However,d espite ubiquitous utilization, the ability to foresee when and how this reaction will occur is still lacking. Indeed, the love-hate relationship between synthetic organic chemists and dehydrogenative coupling is strongly related to the fact that it works with stunning efficiencyi ns ome cases, and that it fails in many others.A lthough we presented acomprehensive overview on the century-long history of the Scholl reaction in 2013, [3] asignificant amount of experimental data in various versions of oxidative aromatic coupling has been accumulated within the last seven years.A tt he same time,t hese studies are increasingly accompanied by DFT calculations,w hich often, post-factum, prove that the unanticipated course of areaction really was to be expected as far as energies of transition states are concerned. Unfortunately, because of space limitations,n ot all the interesting results could be included in this Review.T he photocyclodehydrogenation of stilbenes and derivatives of o-terphenyls, [7,8] Oxidative aromatic coupling occupies afundamental place in the modern chemistry of aromatic compounds.Itisamethod of choice for the assembly of large and bewildering architectures.C onsiderable effort was also devoted to applications of the Scholl reaction for the synthesis of chiral biphenols and natural products.The ability to form biaryl linkages without any prefunctionalization provides an efficient pathwaytom any complex structures.A lthough the chemistry of this process is only nowbecoming fully understood, this reaction continues to both fascinate and challenge researchers.This is especially true for heterocoupling, that is,o xidative aromatic coupling with the chemoselective formation of aC À Cb ond between two different arenes. Analysis of the progress achieved in this field since 2013 reveals that many groups have contributed by pushing the boundary of structural possibilities,e xpanding into surface-assisted (cyclo)dehydrogenation, and developing new reagents. although very interesting and often complementary to the Scholl reaction, will not be described here for this reason. This Review is comprised of four sections that deal with intermolecular oxidative aromatic coupling,t he intramolecular Scholl reaction, on-surface (cyclo)dehydrogenation, and an outlook summarizing progress from 2013 until April 2019. Scheme 1d epicts the general case of the oxidative coupling of arenes and explains the two generally accepted mechanisms:v ia arenium cation and radical cation intermediates.

Intermolecular Oxidative Aromatic Coupling
In the following section we will focus on key achievements in the field of intermolecular oxidative aromatic coupling that have appeared in the literature since our previous review was published in 2013. Occasional references to earlier work will be mentioned where appropriate.

Oxidative Homocoupling of Arenes and Heteroarenes
Among the numerous oxidants typically used for the construction of anew CÀCbond in an oxidative manner,the most frequently applied is iron(III) chloride. [9] New reagents are,h owever, continually proposed for homocoupling processes under oxidative conditions.I ndeed, ag raphene oxide (GO)/BF 3 ·OEt 2 system is able to promote oxidative C À H/C À Hc oupling between two electron-rich arenes in as elective way. [10] Theu tility of boron(III)-based Lewis acids presum-ably relies on the activation of epoxy sites on aGOsurface to form active radical species.E PR studies support ar adical pathway for this transformation. An oxidative coupling process for simple 1-or 2-substituted naphthalene derivatives can also proceed in the presence of AgSO 4 , [11] albeit in moderate yields in most cases.N evertheless,u nder these conditions,1 -(trifluoromethyl)naphthalene gives 5,5'-bis(trifluoromethyl)-1,1'-binaphthyl in 17 %yield, thus showing that the oxidizing power of silver(II)-based systems can partially overcome the electronic limitations caused by an electronwithdrawing CF 3 group.T he corresponding binaphthyls derived from 1-nitro-and 1-cyanonaphthalene are not formed under these conditions.
Molybdenum pentachloride is as elective,o ne-electron oxidizing reagent frequently employed in many batch oxidative coupling processes, [12] and more recently under continuous-flow conditions. [13] In most MoCl 5 -mediated reactions of this type,undesired chlorination can be successfully avoided, as the CÀCcoupling is much faster than other side reactions. However,f or highly electron-rich substrates or when the coupling process proceeds slowly,c hlorination becomes an issue. [14] Theapplication of MoCl 5 together with aLewis acid (usually TiCl 4 ), which is believed to bind the coformed chloride anions,i ncreases the overall efficiency of the C À C coupling, [15] but this beneficial effect is not general. To solve this problem, the Waldvogel group designed [16] the two dinuclear molybdenum(V) complexes 1 and 2 (Figure 1), which were prepared from MoCl 5 and either 1,1,1,3,3,3hexafluoroisopropanol (HFIP) or 2,2,2-trifluoroethanol (TFE) in 95 %a nd 97 %y ield, respectively.A ccording to electrochemical measurements and DFT calculations,o nly complex 1 has an oxidizing power comparable to that of MoCl 5 [E p (MoCl 5 ) = 1.16 V; E p (1) = 1.22 V, versus FcH/ FcH + ;F cH = ferrocene],w hile electron transfer from 3,4dimethoxytoluene to complex 2 should be strongly prevented because of the low potential value [E p (2) = 0.31 V, versus FcH/FcH + ]and the sterically congested coordination sphere. Problematic substrates were subjected to oxidative coupling reactions mediated by MoCl 5 ,M oCl 5 /TiCl 4 ,o rc omplex 1 (Table 1). In all cases,t he authors obtained considerably higher yields for reactions mediated by complex 1 compared with the other two systems and this fact was associated with such factors as the lower chlorine content of the reagent 1 (thus avoiding chlorination), the lower nucleophilicity of the HFIP ligands compared to chloride,a nd the considerably higher reaction rate of the CÀCcoupling compared with side processes induced by the higher oxidation potential of complex 1.
It is not only molybdenum(V) complexes that are useful mediators in the oxidative formation of new C À Cb onds.A n electrochemical system consisting of an active molybdenum anode,agraphite cathode,and HFIP as amediator was found to be highly effective in the dehydrogenative homocoupling of simple electron-rich arenes. [17] Thee laborated method tolerates ab road scope of arenes and is particularly important, especially for environmental reasons,a si td oes not generate al arge amount of reagent waste.
An interesting discovery was made by Boyd and Sperry, [18] who examined the influence of various oxidizing agents on the dimerization process of hemidendridine acetates of type 6 (Scheme 2). Under the influence of aw ide range of typical oxidants [FeCl 3 ·SiO 2 ,A g 2 O, Pb(OAc) 4 ,K 3 [Fe(CN) 6 ], PhI-(OAc) 2 (PIDA)] 6 decomposes,a nd no trace of ad imer is detected in the reaction mixture.N evertheless,t he 6,6'coupled, symmetrical dimer 8 is formed exclusively through the oxidative dimerization of 6 mediated by (tBuO) 2 in toluene at 130 8 8Cf ollowed by protection of the hydroxy groups in 7.T his is the result of an ortho-ortho coupling, which is usually observed for phenols in the absence of steric hindrance [19] or catalyst control. [20] Completely different regioselectivity is observed if an indole precursor bears an iPrO substituent. Under Scholl-type conditions,t he best result was obtained with the MoCl 5 /TiCl 4 system, thus 6 was successfully transformed into 4,4'-bistryptamine 9 in 32 % yield. Besides 9,s everal other unsymmetrical products were isolated from the reaction mixture in atotal yield of 14 %. In this case,t he reaction outcome is undoubtedly governed by the bulky OiPr group,which enforces the dominant para-para coupling.S uch ar egioselectivity can also be achieved by blocking the ortho positions relative to the OH group,aswas recently shown by Porco and co-workers. [21] Theo xidative dimerization of larger phenols represents one of the most convenient pathways toward complex 2,2'dihydroxybiaryl compounds.According to the Tsubaki group, butterfly-shaped molecule 11 can be obtained by the Cu IImediated dimerization of dinaphthofuran-6-ol ( Figure 2). [22] Thedihedral angle between the two central naphthyl moieties can be altered by chemical modification of the central region; for example,acid-catalyzed dehydration involving the central OH groups delivers an additional furan system, which in turn decreases the dihedral angle from 86.48 8 to 14.68 8,aspredicted by DFT methods.T he protected 1,1'-bi-2-pyrenol (12, Figure 2) can be prepared by the Fe III - [23] or Cu II -mediated [24] oxidative dimerization of the protected precursor of 2pyrenol. After dimerization, diastereomers of type 12 can Figure 1. Structures of newly designed Mo-based mediators for oxidative coupling. [16]  be effectively separated [24] using conventional chromatography and then be deprotected to deliver optically pure 1,1'bi-2-pyrenols.A nother complex phenol 13,b ased on the naphtho[2,1,8-def]coumarin scaffold, was synthesized by employing aF eCl 3 /(tBuO) 2 system. [25] Numerous attempts to perform the second coupling process to generate ah eterocyclic analogue of 2,4:9,11-dinaphthoperylene were ineffective.I nc ontrast, 3,6-dibromo-2,7-dihydroxynaphthalene dimerizes selectively [26] at C1 and C8 to form am ixture of dihydroxyperylenequinones,w hich after reduction and alkylation affords the octasubstituted perylene analogue 14.
Anilines,asaconsequence of their electron-rich character and thus lower oxidation potentials,should undergo oxidative aromatic coupling more easily than phenolic derivatives. Indeed, treatment of some secondary and tertiary anilines with p-chloranil as an oxidizing agent [27] produces dimerization products 15-19 (Scheme 3). From as tructural point of view,t he method tolerates av ariety of functional groups (even those with electron-withdrawing character) as well as substrates with sterically hindered reactive sites.I np arallel, Kita and co-workers proved [28] that the dimerization of 1naphthylarylamines,1 -naphthyldiarylamines,o r2 -naphthyldiphenylamine mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) takes place selectively at the naphthyl site of the molecule.S imilar to the p-chloranil-mediated method, these conditions are also applicable when steric hindrance is present within as ubstrate molecule.
Scheme 4d epicts ac atalytic approach for the oxidative homocoupling of anilines. [29] In this case,asystem comprised of rhodium adsorbed on carbon, air,a nd TFAa sasolvent showed the highest efficiency.Biaryl amines 20-26 (including p-expanded analogues 20 a-d)w ere obtained selectively in high to excellent yields (up to 99 %). Interestingly,w hen HFIP was used as as olvent, the authors obtained the carbazole-based compound 21 as the sole product in 70 % yield. Theo xidative cross-coupling of aromatic amines was also reported by Pappo and co-workers as well as the Shindo group. [30,31] In 2017, Knçlker and co-workers investigated the reactivity of diarylamines of type 27 towards iron(III)-based catalysts:hexadecafluorinated iron-phthalocyanine (FeF 16 Pc) and iron(III) chloride hexahydrate (Scheme 5). [32] By using FeF 16 Pc as ac atalyst, 2,2'-di(arylamino)biaryls 28,t etraarylhydrazines 29,a nd 5,6-dihydrobenzo[c]cinnolines 30 can be obtained in reasonable yields.T he selectivity is governed by the use of acidic or basic additives.Namely,inthe presence of aFeF 16 Pc/MsOH system, diarylamines 27 give exclusively the 2,2'-coupled products 28.B yc hanging the character of the additive from acidic to basic, 27 undergoes N À H/N À H oxidative coupling to form the tetraarylhydrazines 29.Unexpectedly,when 27 was treated with astoichiometric amount of FeCl 3 ·6 H 2 O, spiro-products 31 were obtained in reasonable yields.
Recently,V enkatakrishnan and co-workers [33] found that, whereas carbazoles containing electron-donating groups form 3,3'-coupled products,s ubstrates bearing electron-withdrawing groups tend to form predominantly 1,1'-coupled molecules.T he dimerization of N-phenylcarbazole can also be achieved using Eatonsr eagent (composed of 7.5 wt % phosphorus pentoxide in methanesulfonic acid). [34] Thesynthesis of large graphenic structures from relatively simple molecules is usually not astraightforward task. Among the many approaches leading to nanographenes,the benzene ring seems to be an ideal candidate for the bottom-up synthesis of such structures. [5,6,35,36] Zarabin and co-workers attempted [37] the construction of nanographene sheets from benzene at al iquid-liquid interface.A ccording to their strategy,asingle benzene ring should undergo FeCl 3 -mediated oxidative coupling to give oligo(paraphenylene) and/or poly(paraphenylene). Thep oly(paraphenylene) fractions should spontaneously migrate to the water-benzene interface, where the second polymerization step that creates lateral chains occurs.I nt he final step,as eries of intramolecular oxidative coupling processes between adjacent phenyl rings within the branched polymer takes place.T he proposed method allows the preparation of large graphene nanosheets with asurface area of about 800 nm 2 .
Recently,o xidized active carbon/oxygen, [38] 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/MsOH, [39] and NOBF 4 /oxygen [40] systems were found to be applicable for the construction of 2,2'-o r3 ,3'-coupled motifs starting from benzofused heterocycles such as indole,b enzothiophene,o r benzofuran. Short-chain oligopyrroles constitute outstanding substrates for the formation of various pyrrolic macrocycles, which may vary significantly in their electronic properties and metal-binding properties. [41][42][43] Anand and co-workers investigated the reactivity of benzo-dipyrromethanes under oxidative conditions (Scheme 6), [44] and they uncovered that the reaction outcome highly depends on the exact structure of the dipyrromethene substrate.T he DDQ-mediated oxidation of monobenzo-dipyrromethanes 32 to the corresponding dipyrromethenes 33 (Scheme 6A)f ollowed by treatment with Cu(OAc) 2 leads to cyclic trimers of type 34.I ft he same sequence was applied to 32 b in high dilution, am ixture of dimer 35 and trimer 34 b could be obtained. Subjecting 36 to the same reaction sequence (Scheme 6B)r esulted in cyclodimer 37 containing two fused seven-membered rings in the central part of the molecule.F inally,t he stepwise,D DQ/ Cu(OAc) 2 -mediated oxidation of dibenzo-dipyrromethane 38 gives access to the unsymmetrical, acyclicd imer 39 (Scheme 6C)w ith six-and seven-membered rings at its core.

Oxidative Cross-Coupling of Arenes and Heteroarenes
Cross-coupling processes occurring between two different arenes could potentially afford three different products (or more,ifagiven substrate has two inequivalent reactive sites). To reduce the number of possible products,Papposmodel [46] based on an interplay between global nucleophilicity and oxidation potentials may be considered. Another system consisting of asalen-based catalyst (56)and atom-economical oxygen as the terminal oxidant was found to be broadly effective in oxidative cross-coupling reactions to give compounds 50-55 (Scheme 8). [20] According to Kozlowski, the 2,6disubstituted phenol 48 should be applied as the substrate to carry out as elective cross-coupling process and reduce the number of possible products. [47] It was assumed that such aphenol (called Ty pe I) should bind selectively at its para site to al ess-hindered site of am etal-bound radical or radical cation of the second phenolic partner (49). Taking into account the regioselectivity of the method, substrates of type 49 were assigned as Ty pe II (2,4-, 3,4,5-, 3,5-, and 2,3,5substituted phenols) and Ty pe III (2,5-substituted phenols), as they provide para-ortho (p-o)a nd para-para (p-p)c oupled products,respectively.
Electrochemical oxidation is currently being considered as ag reen alternative for classical oxidative aromatic coupling,b ecause such am ethod does not require am etalbased catalyst or as toichiometric amount of an oxidant to form the crucial intermediate-a radical cation. However,the selective generation of an ew C À Cb ond between two different aryl moieties under either classical or electrochemical conditions is challenging due to astrong tendencytoform homocoupled products.
Recently,W aldvogel and co-workers proved that the use of HFIP as am ediator,c ombined with ab oron-doped diamond electrode (BDD) as the anode constitutes apowerful system for selective phenol-arene cross-coupling under electrochemical conditions. [48][49][50][51][52] Thei mportance of this specific solvent and the source of selectivity can be attributed to the strongly different solvation of the individual coupling partners and, therefore,t he decoupling of the oxidation potential from the nucleophilicity.T he efficiency and selectivity of the cross-coupling process can be improved when HFIP/methanol or HFIP/water mixtures are used as mediators. [53,54] Fore xample,t he electrochemical oxidation of Nprotected aniline derivatives using HFIP/methanol as amediator and glassy carbon as the anode material leads to avariety of unsymmetrical 2,2'-diaminobiaryls in moderate to good yields and excellent regioselectivity. [55] Easily removable protecting groups including Boc, acetyl, benzoyl, pivaloyl, and trifluoroacetyl are fully compatible with the electrochemical environment;t hus,a fter deprotection under mild conditions,t his method provides expedient access to important structural motifs.

Reviews
Recently,W aldvogel and co-workers successfully elaborated an electrochemical alternative for the arylation of sulfur-containing heterocycles.T hiophenes [56] and benzothiophenes [57] were effectively coupled with phenol derivatives to form biaryl systems with high selectivity and efficiency. Importantly,with 2-as well as 3-substituted benzothiophenes they obtained abroad scope of products in yields up to 88 %. In the case of thiophenes,a pplying an excess of phenolic substrate (3 equiv) leads to diarylated products in high yields.
Hypervalent iodine(III)-based compounds serve as excellent oxidizing agents in oxidative aromatic coupling processes, [58,59] and they are typically used in stoichiometric or excess amounts.T he first organocatalytic version of an oxidative cross-coupling reaction between sulfonylanilides and aromatic hydrocarbons was developed by the Kita group ( Figure 3). [60] During this process,t he organocatalyst 57 based on a2 ,2'-diiodobiaryl scaffold is oxidized to its hypervalent iodine(III) analogue 58 by mCPBA. After the crosscoupling reaction, the organocatalyst is then regenerated by the same means as its activation. Thep rocess is slower and al ower yield was obtained when 0.75 equiv of 58 was used instead of acatalytic amount of 57.Aseries of derivatives 59-62 containing naphthyl or phenanthryl substituents were obtained using the organocatalytic method, with yields of up to 99 %.
In their follow-up publication, the Kita group explored simple iodobenzenes as potential organocatalysts in oxidative phenol-arene or phenol-phenol cross-coupling reactions. [61] Ac atalytic system consisting of 4-iodoanisole (10 mol %), oxone (1.2 equiv), 18-crown-6, and CH 3 COOH in HFIP was shown to be the most efficient method. High regioselectivity and broad substrate scope represent indisputable advantages of this method. According to the studies of More and Jeganmohan, [62] oxone mixed with the phase-transfer catalyst Bu 4 N + HSO 3 À in acetic acid also constitutes aselective system for the formation of unsymmetrical biphenols;h owever,t he yields obtained were only moderate.
Recently,P appo and co-workers made as ignificant contribution to this field by the discovery [46,63] that, depending on the solvent used during an oxidative coupling process,t wo different products (64 and 65)c an be obtained starting from 2,6-dimethoxyphenol (63;Scheme 9, top). In aHFIP solution, the initially formed radical [63ÀH]C is stabilized to ag reater extent than in DCE, thus it reacts with the most nucleophilic site of phenol 63 and leads to 64 through ar adical-anion coupling mechanism. In DCE, [63ÀH]C is poorly stabilized, and it undergoes ar apid recombination process through ar adical-radical coupling mechanism. Based on this finding, the authors developed ap redictive model based on the interplay between the theoretical global nucleophilicity (N) and the susceptibility to oxidation (derived from ad irect comparison of the oxidation potentials measured in HFIP). [46] According to this model, an efficient cross-coupling process between phenols A and B can be performed as long as: 1) one of the phenols (A)c an be selectively oxidized to ac orresponding phenoxyl radical (E ox )i nt he presence of the second phenolic partner B; 2) the second phenolic partner (B)e xhibits am ore pronounced nucleophilic character (that is when N B > N A or DN > 0).
As et of unsymmetrically coupled biaryls 66-68 was selectively constructed using this model when DN > 0 (Scheme 9, bottom). When DN < 0, the selectivity of this process decreases,thus only moderate yields are achieved for cross-coupling reactions (e.g.p roducts [69][70][71]. During the carbon-carbon bond-forming step in the FeCl 3 /(tBuO) 2 / HFIP-mediated process,b oth phenolic components are attached to the metal center.Asanextension of the proposed model, the same group later discovered [64] that as ystem consisting of an iron meso-tetraphenylporphyrin chloride (Fe[TPP]Cl) complex and HFIP allows for the selective oxidative cross-coupling of readily oxidized phenols with poorly nucleophilic phenolic partners (DN < 0). It is believed that the high selectivity of the process results from the presence of as ingle available coordination site for phenol binding on the metal center in Fe[TPP]Cl.
Thea uthors have demonstrated that the use of the iron(III)/(tBuO) 2 couple in fluorinated solvents enables many valuable cross-coupling products to be obtained, such as biaryls 72-73 and 75-76,a sw ell as triaryl 74 (46 %y ield; Figure 4). [46,63] Importantly,polycyclic aromatic hydrocarbons larger than naphthalene,s uch as anthracene,p yrene,a nd benzopyrene,are also reactive in this transformation and lead to 77-79.T his study was recently further extended to include cross-coupling catalyzed by Co II -salen and Cr III -salen complexes. [65,66] As shown in Figure 4, the reaction of 3,5-dimethoxyphenol and 1,3,5-trimethoxybenzene (2.1 equiv) gives the bisarylated product 74 in reasonable yield. Intrigued by this result, the same authors evaluated the dilemma of polyarylation in depth (Scheme 10). [67] According to their study,t he first coupling reaction of the phenolic substrate 80 occurs at the available ortho/para position(s) relative to the hydroxy group. Then, they found that the subsequent reaction strongly depends on the character of the substituent R. If R = H, the next coupling process leads to ortho-arylated derivative 82.In the case of Rbeing amethyl group,the second/third arylation reaction exhibits meta selectivity,f inally providing ac om-pound with an exemplary substitution pattern of type 83. When Risamethoxy group,the third arylation reaction tends to proceed chemoselectively at the OH group to form aC À O coupling product 84.T he EPR studies performed on the key persistent phenoxyl radicals clearly demonstrated that the coupling selectivity strongly correlates with the distribution of high spin density over the above-mentioned radicals.
Polyarylated phenolic derivatives can also be assembled by the iron(III)-catalyzed functionalization of 4-aryl-4methoxy-2,5-cyclohexadienones 85 (Scheme 11, top). [68] Although this reaction is not an oxidative aromatic coupling, but rather ap olar reaction of an electrophile 85 with arene nucleophiles,w ed ecided to present it here for the sake of completeness of strategies leading to polyarylated phenols. Substrates of type 85 were prepared using the PIDAmediated oxidation of the corresponding 4-arylphenols in the presence of MeOH. [69,70] Initially,c ompounds 85 are arylated at the a-position relative to the keto group in the presence of ac atalytic amount of iron(III) chloride,t hereby leading to the 2,4-diarylphenolic derivatives 86-90.However, for asubstrate formed by the PIDA-mediated oxidation of 4methyl-1-hydroxynaphthalene in MeOH they obtained amixture of a-a nd b-arylated products in yields of 76 and 20 %, respectively.P roducts of monoarylation, that is 86 a or 86 c, can be subsequently oxidized to 91 a,b and arylated again to give 2,4,6-triarylphenolic molecules 92-93 (Scheme 11, bottom). One major drawback of the above method is that as ignificant excess of the arene (Ar 2 Hu pt o1 0equiv) is required to achieve monoarylation.
It is well known that 9-phenanthrenol undergoes an oxidative aromatic homocoupling reaction at C10 under the influence of Cu II species. [71,72] Wang et al. found [73] that 9methoxyphenanthrene (94)shows asimilar reactivity towards 2-methoxynaphthalene derivatives in the presence of (NH 4 ) 2 S 2 O 8 ,w ith C10/C1-linked molecules 95 being formed with excellent regioselectivity (Scheme 12). Interestingly, when 2-naphthylamine derivatives were employed in this cross-coupling reaction, C3-arylation products 96 were obtained in good to excellent yields.A ccording to DFT calculations employed in this study, 94 and 2-methoxynaphthalene cation radicals have the highest spin density distribution at positions C10 and C1, respectively,a nd they follow ar adical coupling pathway leading to the C10/C1 linked product (Scheme 12, bottom). In contrast, 94 reacts with 2naphthylamine at the most electrophilic position (C3), because the oxidation potential of naphthylamine increases significantly upon protonation in acidic media, thereby preventing the effective formation of aradical cation.
Kita and co-workers successfully performed as eries of PIFA-mediated intermolecular oxidative coupling processes between pyrrole derivatives and 3,4-ethylenedioxythiophene ( Figure 5). [74] Thed imers of type 97 were synthesized in moderate to good yields with excellent regioselectivity.Inthe case of dimers containing an unprotected pyrrole unit, intramolecular hydrogen bonds enforce high coplanarity of both subunits,asproven by X-ray crystallography,potentially allowing these dimers to serve as excellent substrates for efficient conducting polymers.

Enantioselective Synthesis of Chiral Biaryls
Hindered rotation around the C aryl -C aryl bond, such as in binaphthyl or ortho-substituted biphenyl derivatives,g ives rise to axial chirality,w hich is present in many natural products [75][76][77][78] and is the basis of various asymmetric catalytic systems. [79] Hence,i ti sn ot surprising that the oxidative coupling of arenes,b eing one of the simplest ways to synthesize biaryls,w as quickly recognized as ap otential method to access optically active products. [47,76,78] Early successful reports were based on the use of copper complexes with chiral amines as catalysts for the enantioselective synthesis of BINOL derivatives under aerobic conditions (Scheme 13). [80][81][82][83] Thee nantioselectivity was significantly improved after mononuclear [84,85] and binuclear [86,87] vanadium complexes were introduced. [88] Recently,E gami and Katsuki developed chiral iron(salan) complexes (Scheme 13), which afforded unsubstituted BINOL and 3,3'-disubstitued derivatives with an enantiomeric excess of 64 %a nd up to 97 %, respectively. [89] Progress in the asymmetric synthesis of biaryls has been briefly summarized in recent articles. [47,88,90,91] Themost important recent contributions are presented below.
Pappo and co-workers developed an ew chiral iron complex 99 bearing three BINOL-phosphate ligands which  turned out to be av ery efficient catalyst for the enantioselective homo-and cross-coupling of 2-naphthols. [92] Scheme 14 presents selected examples of BINOLs (98 a-f) prepared with good ee values using as little as 2.5 mol %o f catalyst 99 in am ixture of DCE and HFIP as as olvent and with di-tert-butyl peroxide (1 equiv) as at erminal oxidant. Importantly,t he authors have also found that enantiopure BINOLs undergo racemization in the presence of Fe III and Cu II salts,w hich may reduce the enantiomeric excess of the products from the oxidative coupling.I nt he case of crosscoupling,t he reaction yields were significantly lower due to the formation of homocoupled side products.N evertheless, this is one of only af ew examples of enantioselective oxidative cross-coupling reactions to date.
Dinuclear vanadium catalysts are among the most efficient examples for the enantioselective syntheses of BINOLs, [86][87][88]93] useful even in the dimerization of PA Hbased phenols. [94] However,recent studies have revealed that chiral mononuclear vanadium(V) catalysts are also useful. Takizawa, Oh, and co-workers found that 4-substituted 2naphthols undergo oxidation with oxygen in the presence of mononuclear catalyst 101 or dinuclear 102 to give either R or S enantiomers,r espectively,o fB INOLs 100 in good yields and high ee values (Scheme 15). [95] Themononuclear catalyst 101 had to be used in higher loadings (5 mol %) and resulted in slightly lower ee values.
Compound 107,a lso am ononuclear vanadium complex, was found by Takizawa, Sasai, and co-workers to catalyze the enantioselective formation of oxa [9]helicenes 106 in one step from 2-hydroxybenzo[c]phenanthrenes 103 (Scheme 16). [96] In this transformation, 107 acts simultaneously as both aredox catalyst (enantioselective aerobic oxidative coupling) and Lewis acid (metal-mediated intramolecular cyclization) Scheme 13. Early catalytics ystemsf or the enantioselective synthesis of BINOL derivatives by the oxidative dimerization of 2-naphthols. catalyst. Theauthors proposed that this process may proceed via intermediates 104 or 105,a lthough these could not be detected in the reaction mixture.T his method tolerates ab road scope of substrates,g iving (M)-oxa [9]helicenes with ee values up to 94 %.
Although numerous chiral catalysts have been developed for the asymmetric synthesis of BINOLs by oxidative coupling,t he enantioselective preparation of chiral biphenyl derivatives has remained challenging until very recently. Kozlowski and co-workers addressed this issue and performed an extensive catalyst optimization study using dinuclear vanadium catalysts as astarting point. [91,97] It turned out that nitro-substituted mononuclear vanadium complex 109 actually provided the best results,especially in the presence of acetic acid or lithium chloride as additives (Scheme 17). A series of biphenols of type 108 were obtained in good yields and moderate ee values. N-Benzyl-2-hydroxycarbazoles also reacted under similar conditions to give the corresponding 1,1'-coupled dimers enantioselectively.K ozlowski and coworkers utilized the new catalyst in the total synthesis of chaetoglobin, where ak ey chiral biaryl intermediate was prepared by atroposelective oxidative dimerization of phenols catalyzed by 109. [98] Very recently,T akizawa, Sasai, and co-workers developed ad inuclear vanadium complex that mediated the oxidative homocoupling of various 5-arylresorcinols to furnish the corresponding biaryls with up to 98 % ee. [99]

Metal-Catalyzed and Metal-Mediated Intermolecular Oxidative Coupling of Electron-Poor Arenes
In terms of both the mechanism and the scope,the metalcatalyzed intermolecular dehydrogenative coupling of electron-poor arenes differs significantly from classic oxidative aromatic coupling.H owever,w eh ave decided to include an overview of this synthetic methodology,with an emphasis on copper and rhodium catalysis as well as af ew selected examples of palladium-mediated reactions which have been more generally reviewed recently. [100][101][102][103][104]
Miura and co-workers realized the copper-mediated regioselective dehydrogenative biaryl coupling of naphthylamides and 1,3-azoles using copper(II) acetate in the presence of pivalic acid. [106] As ar epresentative example,t he reaction of 113 with benzoxazole leading to 114 is given in Scheme 18. Deuterium labeling experiments suggest that the metalation takes place at the benzoxazole first, with the species formed then undergoing ad irected C À Ha ctivation at the naphthalene derivative.

Rhodium
In the last few years some interesting reports on rhodiumcatalyzed dehydrogenative arene coupling reactions have appeared, often within the context of directed CÀHa ctivation. You, Lan, and co-workers reported the chelationassisted rhodium(III)-catalyzed oxidative C À H/C À Hc rosscoupling of indoles and pyrroles with heteroarenes preferentially at the C2-position (Figure 7). [107] Their strategy allows the selective coupling between an electron-rich heteroarene with ad irecting group and both electron-rich and electrondeficient heteroarenes.F or example,2 -pyrimidyl-protected indoles or 2-methylpyrrole react with electron-poor heterocycles in the presence of a[ Cp*RhCl 2 ] 2 /AgSbF 6 catalyst system to afford coupling products 115-120.C losely related reactions were published by Kambe and co-workers at almost the same time. [108] More recently,t he procedure has been extended to the synthesis of mono-and bisarylated phenols. [109] Scheme 17. Reaction conditions:a )109 (20 mol %), AcOH (6.25 equiv) or LiCl, O 2 ,t oluene,08 8Cor258 8C. In the context of directed CÀHa ctivation, Youa nd coworkers also reported the rhodium-or ruthenium-catalyzed oxidative CÀH/CÀHc ross-coupling between various heterocycles and 2-aryl-substituted pyridines or quinolines in the presence of [Cp*RhCl 2 ] 2 or [{Ru(p-cymene)Cl 2 } 2 ]a sc atalysts. [110] Three exemplary products 121-123 are presented in Figure 7. Similar reactions were reported with oxime ethers as substrates. [111] Later the same group reported the use of the Wilkinson catalyst for the ortho-heteroarylation of pivaloyl anilides. [112] Li and co-workers developed rhodium(I) catalysts for the regiospecific homodehydrogenative coupling of aromatic carboxylic acids in water (Scheme 19). [113,114] Thedimerization of variously substituted benzoic acids upon reaction with the chloro(norbornadiene)rhodium(I) dimer as ac atalyst and manganese dioxide or sodium chlorite as the oxidant gave coupling products of type 124 in good yields.Inasubsequent report, the authors showed that cross-dehydrogenative coupling is also possible under similar reaction conditions if one of the carboxylic acids is electron-rich. [115]

Palladium
Most of the reported metal-catalyzed or -mediated CÀH/ CÀHd ehydrogenative coupling reactions involve palladium as the catalyst metal. There are some reports on palladiumcatalyzed arylations by coupling an arene with another bearing an ortho directing group. [100][101][102][103][104] In this context, Song,Y ou, and co-workers reported reactions of anilide derivatives with arenes,w hich were catalyzed by palladium-(II) acetate in the presence of ammonium peroxodisulfate as the oxidant and TFAa st he solvent (Figure 8). [116] Crosscoupled products such as 125-127 were obtained in yields ranging from 31 %to95%.Aclosely related reaction, namely the palladium(II)-catalyzed dehydrogenative coupling of arenes with indolines at C7, has also been reported (products 128;F igure 8). [117] Guan and co-workers showed that biaryls of type 129 can be synthesized by coupling tertiary benzamides with arenes by utilizing the in situ generated palladium(II) triflate as the catalyst and dipotassium peroxodisulfate as the oxidant (Figure 8). [118] Homo-and cross-dehydrogenative coupling reactions yielding biaryls were also reported by Zhang and Rao,w ho used HFIP as the solvent and sodium periodate/dipotassium peroxodisulfate as oxidants. [119] Homodimers of types 130-132 as well as unsymmetric biaryls (e.g. [133][134][135]were obtained in good yields (Figure 9).
In an interesting mechanochemical approach, Xu and coworkers showed that the rates of dehydrogenative coupling reactions can significantly increase when ball milling is used instead of conventional heating. Long reaction times of up to 24 hf or conventional reactions were reduced to 1h,w ithout the need for external heating. [120] Although the dehydrogenative coupling reactions mentioned so far involve benzene derivatives that result in biphenyl-derived products,t here are also reports on the coupling of heterocycles.Y ua nd co-workers reported an interesting coupling reaction of pyridines to afford 3,3'bipyridyl derivatives (e.g. 136)inaddition to aminor amount of the 2,3'-isomer. [121] Thereaction is catalyzed by palladium-

Intramolecular Oxidative Aromatic Coupling
Although numerous impressive examples have been known for al ong time,o nly in recent years has the methodology for the intramolecular oxidative coupling of arenes reached its synthetic potential and become awell-established tool used in avariety of applications.The growing importance of research in such fields as organic electronics,nanotechnology,a nd bioimaging,h as led to an increased demand for simple and effective methods for the creation of intramolecular C aryl -C aryl bonds.Often simply (but not entirely correctly) referred to as the "Scholl reaction", the intramolecular oxidative coupling of arenes is av ersatile and widely used method for the synthesis of various polycyclic aromatic hydrocarbons (PAHs), including so-called nanographenes, as well as expansions/planarizations of p-conjugated systems and for the preparation of strained, curved, or twisted systems.F or space reasons,t he application of cyclodehydrogenation in the synthesis of small-molecule targets is presented in the Supporting Information.

Large Planar PAHs, Expanded Acenes, and Nanographenes
Perhaps there is no better way to demonstrate the potential of intramolecular oxidative coupling methods than in the syntheses of large polycyclic aromatic hydrocarbons and nanographenes,w here multiple (sometimes hundreds or even thousands) C aryl -C aryl bonds are formed in as ingle operation. It is easy to imagine that as imilar goal would be impossible to achieve using alternative methods of C aryl -C aryl coupling,s ince it would require the presence of numerous activating units (e.g.h alides,b oronic acids/esters,e tc.) strategically positioned over the precursor molecules.
One of the most important examples is hexa-peri-hexabenzocoronene (HBC, 138,R = H; Figure 10). Although HBC and its derivatives had been obtained previously,t he yields were typically very low,and it was not until Müllen and co-workers developed the Cu II /AlCl 3 or FeCl 3 -promoted oxidation of hexaphenylbenzenes that HBC derivatives could be obtained in good yields. [36] Thel atter conditions in particular,w here FeCl 3 is dissolved in nitromethane prior to its addition to asolution of the precursor in dichloromethane, provide the best yields for the broadest scope of HBCs (138; Figure 10), [35,122,123] which opened the door to the synthesis of large PA Hs and nanographenes. Figure 10 depicts some recently reported large PA Hs that were synthesized under intramolecular oxidative coupling conditions.T etrabenzocircumpyrene derivatives 139 a-c have been synthesized in good yields using FeCl 3 as an oxidant in aCH 2 Cl 2 /CH 3 NO 2 mixture. [124] Compound 140 is an extended hexabenzocoronene that was obtained by Dichtel and co-workers. [125] Thea uthors observed that the formation of the first four bonds is very fast (Figure 10, blue bonds), thereby providing an isolable partly fused, twisted intermediate,w hich after prolonged exposure to the FeCl 3 oxidant furnishes the final HBC derivative in good yield.
In addition to FeCl 3 ,D DQ in the presence of Brønsted acids (Rathore conditions) is also frequently used in the synthesis of PA Hm olecules by oxidative cyclization. Compounds 141-145 are examples of PA Hs synthesized using DDQ as an oxidant in the presence of triflic or methanesulfonic acid ( Figure 10). [126][127][128][129] In the case of the hexafluorenylfused HBC 143,D DQ/MsOH proved to be more efficient than FeCl 3 (28 %versus 18 %yield). [128] As aconsequence of the presence of twelve hexyl chains pointing out of the PA H plane,t he aggregation of 143 in solution is restricted and it shows good solubility in common organic solvents.
Murakami, Itami, and co-workers have recently developed an interesting method for the palladium-catalyzed annulative dimerization of monochlorinated oligo-para-phenylenes to afford substituted triphenylenes. [130] Thep roducts contain (oligo)phenylene residues in ap arallel orientation. Tw oofthese triphenylene derivatives have been subjected to oxidative cyclization conditions with FeCl 3 in dichloromethane to give the corresponding products 146 and 147 in good yields ( Figure 10). Thea nalogous oxidative coupling of phenylene residues was not possible when two linear oligophenylene moieties were connected by only one covalent bond, thus indicating that the triphenylene core is necessary Scheme 20. Reaction conditions: a) Pd(OAc) 2 (10 mol %), 1,10-phenanthroline(10 mol %), Ag 2 CO 3 (2 equiv), K 2 CO 3 (2 equiv),p yridine, 130 8 8C. to hold the residues in ap arallel orientation to enable the reaction to proceed efficiently.H owever,t he analogous reaction was reported to be successful for as ingly bonded tri-para-phenylene dimer when the subunits were end-capped with octyloxy substituents, [131] thereby furnishing the tetraoctyloxy derivative of 147 in good yield. As imilar approach towards triphenylene derivatives,b ut employing oligo-paraphenylene iodides instead of chlorides,w as independently developed by Shi and co-workers;t he products also underwent oxidative planarization upon treatment with FeCl 3 . [132] Taoa nd co-workers have utilized the FeCl 3 /CH 3 NO 2 / CH 2 Cl 2 system for oxidative cyclization reactions in the synthesis of numerous extended planar and curved PA Hs. [133][134][135][136] Tetranaphthopentacene 148 is one of many interesting examples prepared by this research group ( Figure 10). [135] Roberts,K rische,a nd co-workers have exploited ruthenium-catalyzed diol-diene benzannulation for the construction of various polyphenylene-type PA Hprecursors. [137] Treatment of zigzag-type oligophenylene precursors with FeCl 3 in dichloromethane in the presence of 4 molecular sieves led to the formation of nine new C aryl -C aryl bonds and afforded PA Hs 149 a-d in moderate yields (9-40 %; Figure 10). The presence of nitrogen bridges in 149 d significantly decreased the reaction efficiency.
Müllen, Chen, and co-workers have reported the synthesis of as eries of tetrapyrene-fused benzocoronenes 150 a-c ( Figure 10). [138] All compounds were obtained in very good yields by the FeCl 3 -mediated oxidation of the corresponding tetrapyrenylpentacene-quinodimethanes.
Mastalerz and co-workers reported the synthesis of triptycene-flanked tetrabenzoovalene 151,w hich was obtained in 90 %y ield upon oxidation with aF eCl 3 /DDQ mixture ( Figure 10). [139] As ar esult of the large steric hindrance,t he whole system is contorted and easily loses the two central tert-butyl substituents under acidic conditions. In addition to the structures shown in Figure 10, many other PA Hs have been synthesized using the oxidative coupling method [140][141][142][143][144][145][146][147] which, due to space limitations, cannot be included in this Review.
Weia nd co-workers developed ac onvenient method for the synthesis of threefold symmetrical nanographenes 153 and 154 by reacting 1,3,5-tribenzylbenzene derivatives 152 with aromatic aldehydes in the presence of FeCl 3 as acatalyst/ oxidant and acetic anhydride as ad ehydrant in aC H 2 Cl 2 / CH 3 NO 2 mixture (Scheme 21). [148] Thereaction is acombina- Thei nsitu 1,2-aryl shift often changes the course of the oxidative aromatic coupling.Indeed, 1,2-aryl shifts during the course of oxidative aromatic coupling reactions have been regularly encountered over the last few years. [149,150] Ahighly interesting example was published by Müllen and co-workers during attempts to synthesize tetrabenzo[a,cd,j,lm]perylene 156 by the Scholl reaction of 6,7,13,14-tetraphenylbenzo-[k]tetraphene 155 (Scheme 22). [151] Instead of 156,compound 157 was obtained as aresult of two 1,2-aryl shifts.Müllen and co-workers showed that ar adical cation mechanism is much more likely for the first 1,2-aryl shift. In the following study, the authors utilized the discovered rearrangement in the synthesis of fused dibenzo[a,m]rubicene,abowl-shaped subunit of C 70 fullerene. [152] Another example of this trend has been presented by Hartley and co-workers,w ho have shown that terphenyl 158 undergoes single oxidative coupling and a1 ,2-aryl shift to afford 160 and not hexacycle 159 (Scheme 23). [153] Under oxidative coupling conditions (FeCl 3 or DDQ), acenes bearing aryl groups attached to the central benzene rings generally cyclize to form new five-membered rings. [142,144] Scheme 24 depicts an especially interesting example,w here oxidation of symmetric tetracene 161 led to the unsymmetric product 162 containing two new rings of different sizes:five-and six-membered. [154] Theb ottom-up synthesis of carbon nanoribbons is yet another impressive demonstration of the prowess of intramolecular oxidative coupling.Belonging to the nanographene class,c arbon nanoribbons are ribbon-or tape-like graphene fragments which are highly interesting because of their promising optoelectronic and semiconducting properties. Their syntheses have been extensively reviewed recently. [5,155,156] Figure 11 presents the structures of the two exemplary carbon nanoribbons 163 [157] and 164 [158] obtained in excellent yields by Feng, Müllen, and co-workers from the corresponding polymeric precursors using FeCl 3 as an oxidant in aC H 2 Cl 2 /CH 3 NO 2 mixture.T he precursor for nanoribbon 163 was obtained by Diels-Alder polymerization [159] of an appropriate acetylene-functionalized tetraarylcyclopentadienone monomer.T he weight-average molecular weight (M w ) of the resulting polymer reached 640 kg mol À1 .F eCl 3 -promoted planarization of the polymer furnished the nanoribbon with ac ove-type edge structure and width of 0.7-1.1 nm. [157] Thep oly-para-phenylene scaffold of the precursor for nanoribbon 164 was constructed by Suzuki polymerization. [158] After treatment with FeCl 3 ,t he necklace-like nanoribbon 164 was obtained in high yield.
Recent reports show that large PA Hs,s uch as HBC, triangular C 60 H 42 ,o re ven the hexagonal graphene plate C 222 H 150 ,can be successfully synthesized from the corresponding branched polyphenylene precursors in amechanochemical fashion by grinding with FeCl 3 in aplanetary ball mill. [160]

Dyes and Heterocyclic Polyarenes
Theintramolecular oxidative coupling of arenes typically results in ac onnection of two aromatic rings in ac oplanar orientation, which elongates the conjugated system of pelectrons and usually strongly affects the photophysical properties of the obtained polycyclic aromatic products. Hence,i ti sn ot surprising that this method has been widely used for p-expansion in various organic chromophores and fluorophores.
Coumarins are bright organic fluorophores with multiple applications in fluorescence imaging. [161] Figure 12 presents the structures of p-expanded coumarins obtained by the Scholl reaction or by intramolecular oxidative coupling.T he pentacene-based coumarin dimer 165 [162] and its regioisomer 166 [163] can both be efficiently synthesized from the corresponding precursors through an FeCl 3 -promoted intramolecular oxidative coupling in the presence of acatalytic amount of BF 3 ·Et 2 O. Compound 165 can also be obtained by aphotochemical cyclization;however, the yield of the transformation was considerably lower than the oxidation with FeCl 3 . [162] Pyrrolo [3,2-b]pyrrole is the most electron-rich among the known neutral 10p-aromatic systems. [164] This heterocycle recently gained more attention because of the discovery of an efficient one-step,m ulticomponent synthesis of 1,2,4,5tetraarylpyrro [3,2-b]pyrrole dyes with strong fluorescence. By using this method, 2,5-di(biaryl)-substituted derivatives 167 have been obtained from the reaction of ortho-arylbenzaldehyes with 4-alkylanilines and diacetyl (Scheme 25). [165] These products readily react with FeCl 3 to give the series of pexpanded pyrrolopyrroles 168 a-e.G ryko and co-workers devoted much effort to the synthesis of the bowl-shaped pyrrolopyrrole 171,w hich would have an inverse Stone-Thrower-Wales [166,167] topology (Scheme 25). To meet this goal, compounds 169 and 170 were prepared as precursors for 171,with FeCl 3 used to efficiently close the six-membered and seven-membered rings,r espectively. [168,169] Unfortunately,a ll attempts to convert these precursors into 171 by means of classic organic synthesis failed. Finally,h owever, compound 171 was generated on an Au(111) surface by thermal annealing of the precursor 170 under ultrahigh vacuum (see Section 4). [169] Gryko and co-workers revealed the first case of a1,2-aryl shift for aromatic heterocycles (Scheme 26). [170] Te traarylpyrrolo [3,2-b]pyrrole (TAPP) 172 possessing [1,1'biphenyl]-2-yl substituents attached to the pyrrolic nitrogen atoms undergoes selective double dehydrogenative cyclization accompanied by at wofold 1,2-aryl shift under oxidative aromatic coupling conditions.A saresult, instead of the expected product 174 possessing two seven-membered rings, dye 173 is formed.
Tr eatment of bulky tetrabromo-substituted tetraarylpyrrolo[3,2-b]pyrrole 175 with FeCl 3 gave the spirocyclic cationic fluorene derivative 176 instead of the expected product with new six-membered rings (Scheme 27). [171] Computational studies revealed that, in the case of 175,t he formation of the spiro-five-membered ring is preferred in terms of both the transition-state energy and the relative energy of the product. Steric hindrance is undoubtedly the main reason for the different reactivity of compound 175 compared to its analogues that lack additional substituents on the peripheral benzene rings (e.g. 167;s ee Scheme 25). In ab roader context, these two studies have shown that aC ÀC  Intramolecular oxidative coupling has also been used as ac onvenient procedure for the ring fusion of perylene diimides (PDI), [172][173][174] as well as for p-expansions of BODIPY and aza-BODIPY-based dyes, [175][176][177][178][179] which has led to significant bathochromic shifts of the absorption and emission maxima. Al ibrary of p-expanded imidazoles has been prepared by employing aPIFA/BF 3 ·Et 2 Osystem for the oxidative cyclization of variously substituted 1,2,4,5-tetraarylimidazole derivatives. [180] As ac onsequence of their high electron density,p yrrolebased compounds are often cumbersome substrates for reactions involving strong oxidants and acids. [181] However, the efficient intramolecular coupling of pyrrole rings can be achieved under carefully optimized conditions. [182] Ap rominent example was provided in 2007 by Müllen and coworkers,who synthesized the rim-fused hexapyrrolylbenzene 177 ( Figure 13). [183] Thee lectron-rich nature of pyrrole was evident by the fact that the FeCl 3 -mediated cyclization initially led to an overoxidized dicationic form of 177,w hich could be reduced to the neutral 177 with hydrazine.M ore recently,t he authors have extended this synthetic method to include analogues of 177 with one,t wo,o rt hree pyrrole moieties replaced by benzene units (e.g. 178). [184] Scheme 25.  Stępień and co-workers have synthesized an analogue of 177 with one pyrrole ring replaced by an indole unit (179; Figure 13). [185] Thec yclization was accomplished using tris(4bromophenyl)ammoniumylh exachloroantimonate (BAHA, also known as "Magic Blue"), aradical cation oxidant. Similar to 177,t he oxidation leads to an overoxidized aromatic dication of 179 (62 %y ield), which after reduction with zinc amalgam affords the neutral 179 quantitatively.T he same research group also reported the DDQ-mediated synthesis of compounds 180 and 181,e xpanded derivatives of 177 containing one or two methylene bridges in the outer hexapyrrole rim. [186] Another spectacular case of multiple intramolecular oxidative aromatic coupling involving eight pyrrole units to form at wisted aza-PAH containing two unusual N-doped heptagons was revealed by Uno and coworkers. [187] Osuka and co-workers reported yet another example of an efficient intramolecular oxidative coupling of pyrrole rings ( Figure 14). Tetrapyrrole [8]circulene analogue 182 was prepared by employing aso-called "fold-in" strategy, [188] which is am ethod developed earlier by Stępień and co-workers to construct strained macrocycles by contraction of the larger, less-strained precursors. [189,190] Here,amacrocycle consisting of four pyrrole rings connected by ortho-phenylene moieties was oxidatively contracted to 182 in excellent yield by the action of DDQ and scandium(III) triflate in boiling toluene. Products 183-185 were prepared in asimilar way. [191] Depending on the conditions and oxidant used, the bis-(indolyl)helicene 183 or the closed, nonplanar circulene analogue 184 can be obtained in good yields from the same precursor.The eight-membered ring in the latter case readily forms under the same conditions as those used for the synthesis of circulene 182,whereas the preparation of its open form 183 requires the use of much milder conditions (PIFAin CH 2 Cl 2 at À78 8 8C). Thee fficiencyo ft he DDQ/Sc(OTf) 3 system for pyrrole-pyrrole intramolecular oxidative coupling has also been demonstrated by the synthesis of paracyclophane 186,which contains asegregated donor-acceptor-donor system with stacked tetrafluorobenzene rings as acceptors. [192] Boron-doped polycyclic arenes are gaining more and more attention because of their promising properties and use in organic electronics,l ight-emissive materials,a nd fluorescent sensors. [193,194] Yamaguchi and co-workers have synthesized the first planarized, fully conjugated triarylborane 187 using FeCl 3 -mediated cyclization, which led to the formation of two new bonds between the benzothienyl substituents and an anthracene moiety ( Figure 14). [195] Thes ame group has also used FeCl 3 as an oxidant in the synthesis of alarger PA H containing two boron atoms. [196] Thep olycyclica rene 188 doped with an itrogen-boronnitrogen unit has been synthesized by using DDQ in the presence of triflic acid to efficiently close the seven-membered ring ( Figure 14). [197] Many p-extended porphyrins have been synthesized by inter-o ri ntramolecular oxidative coupling;h owever, they will not be described here due to space restrictions and the fact that this subject has been reviewed recently. [198,199] As reported by Tanaka, Kim, Osuka, and co-workers, similar to porphyrin analogues, meso-meso-linked corrole dimers 189 a-c bearing various aryl substituents can also be oxidatively planarized to the corresponding triply linked products 190 a-c (Scheme 28). [200] Ther eaction was accomplished using DDQ in boiling chloroform and required high dilution of the starting materials to minimize unwanted intermolecular coupling reactions.The cyclization was accompanied by overoxidation, thereby leading to the loss of one NH hydrogen atom in each corrole macrocycle,w hich as ac onsequence became non-aromatic.S imilar overoxidation also occurred in the case of the doubly linked corrole dimer 191,w hich was synthesized under similar conditions. [201] The aromaticity of the corrole ring in both types of dimers, 190 and Figure 14. As election of pyrrole-based and boron-doped heterocyclic polycyclic arenes obtained by oxidativec yclization. Reaction conditions:a)DDQ (5 equiv), Sc(OTf) 3 (5.6 equiv), toluene,r eflux;b)PIFA (2.5 equiv), CH 2 Cl 2 , À78 8 8C; c) DDQ (2 equiv), Sc(OTf) 3 (7 equiv), CH 2 Cl 2 ,R T; d) FeCl 3 (8 equiv), CH 2 Cl 2 ,CH 3 NO 2 ,R T; e) DDQ (2.5 equiv), TfOH, CH 2 Cl 2 ,08 8C. 191,can be restored by reduction with NaBH 4 ;however, they slowly reconvert back to the stable non-aromatic forms in air.

Curved, Twisted, and Strained Structures
Nonplanar,curved, and twisted polycyclicaromatic architectures have attracted considerable attention because of their unusual geometries,s trained structures,a nd interesting photophysical and electrochemical properties,w hich are significantly different from those of their planar analogues. [202] Thesynthesis of curved PA Hs remains challenging because of the large strain. Nevertheless,r ecent years have seen ap roliferation of curved or twisted PA Hs synthesized by the intramolecular oxidative coupling method.
Planar PA Hs naturally consist mainly of fused sixmembered benzene rings.T he introduction of rings of different sizes usually induces curvature to the system. Hence,the presence of five-membered rings usually leads to bowl-shaped compounds with positive curvature (e.g.c orannulene and C 60 ). In contrast, larger seven-and eight-membered rings lead to saddle-shaped systems with negative curvatures (e.g. [7]circulene). Figure 15 presents the structures of saddleshaped PA Hs synthesized under intramolecular oxidative coupling conditions.
In 2013, Sakamoto and Suzuki reported an elegant synthesis of tetrabenzo [8]circulenes 192 a and 192 b by the oxidation of the corresponding macrocyclic octaphenylene precursors with Cu(OTf) 2 /AlCl 3 and FeCl 3 ,r espectively ( Figure 15). [203] This was the second successful reported synthesis of an [8]circulene derivative;t he first report preceded it only by af ew weeks. [204] In Section 3.2 we described the synthesis of at etrapyrrole analogue of 192, compound 182,w hich was obtained by as imilar "fold-in" strategy,b ut using DDQ/Sc(OTf) 3 as an oxidant. [188] In contrast to 182,t he products 192 a,b are saddle-shaped, as evidenced by X-ray crystallography.B yu sing the same approach, Miao and co-workers recently synthesized am uch larger derivative of [8]circulene,asaddle-shaped PA H 193 flanked by two fused HBC moieties ( Figure 15). [205] DDQ in TfOH/CH 2 Cl 2 enabled the formation of all required 14 C aryl -C aryl bonds in one step,t hereby providing 193 in 16-18 % yield. An alternative method to construct the tetrabenzo- [8]circulene scaffold starts with tetraphenyl-substituted tetraortho-phenylenes which already contain ac entral eightmembered ring. These phenylenes are treated with DDQ/ TfOH to effect the oxidative closure of four external benzene rings. [206] This approach is efficient (47-72 %y ield) for the synthesis of variously substituted derivatives of tetrabenzo- [8]circulene that can undergo further functionalization.
have also reported an analogue of 196 with five benzene rings replaced by thiophene rings. [215] Figure 16 presents four examples of bowl-shaped PA Hs synthesized using intramolecular oxidative coupling in the final step.Compound 197 is aderivative of hemifullerene (C 60 half), which was obtained in excellent yield and regioselectivity by Amaya, Ito,a nd Hirao through DDQ/Sc(OTf) 3promoted oxidative cyclization of the precursor derived from the condensation of sumanene with three molecules of benzophenone. [216] Mughal and Kuck synthesized the tribenzotriquinacene-HBC hybrid 198 using the classical Müllen oxidative coupling conditions by employing copper(II) triflate/aluminum chloride in CS 2 ( Figure 16). [217] Thep roduct contains one seven-membered ring formed between the HBC and one of the benzene rings in the triquinacene core. Attempts to synthesize a C 3 -symmetric analogue of 198 containing three HBC moieties failed. [218] Kuck, Chow,and co-workers have,however,reported the syntheses of other bowl-shaped derivatives of tribenzotriquinacene bearing threefold symmetry:c ompounds 199 [219,220] and 200 [221] (Figure 16). Tr iquinacene 199 was obtained in 37 %y ield from an unsymmetric triaryltribenzotriquinacene precursor by oxidative closure of three seven-membered rings upon treatment with DDQ/TfOH. Thep roduct 199 contains an o,p,o,p,o,p-cyclohexaphenylene belt at the rim of the bowl. Even more interesting is the synthesis of derivative 200,arare example of oxidative macrocyclization, which was achieved using similar conditions as for 199,however, in amuch higher yield (ca. 85 %; Figure 16). Theh igh efficiencyo ft he threefold macrocyclization can be attributed to the rigid framework of the tris(triphenyleno)triquinacene system, which spatially prearranges the alkoxyphenyl groups for intramolecular oxidative coupling.
Smith and Lucas have reported the synthesis of interesting tetraarylene-bridged cavitands based on resorcin[4]arene using FeCl 3 or DDQ as the oxidants. [222] Helicenes have fired researchers imagination ever since the first synthesis and resolution of [6]helicene in 1956. [223] Thesynthesis of helicenes has long been dominated by iodinecatalyzed photocyclizations of stilbene derivatives. [224,225] Numerous examples published in recent years clearly show that the intramolecular oxidative coupling can be no worse,or even superior,f or the construction of strained helicene scaffolds,especially for products containing multiple helicene fragments.
Thepioneering synthesis of dibenzo [5]helicene by Durola and co-workers using FeCl 3 as the oxidant indicated that intramolecular oxidative coupling can be av ery efficient method for the preparation of helicenes. [226] By using this strategy the authors have synthesized in high yields the tris [5]helicenes 201 a [226] and 201 b [227] (Figure 17), as well as many other distorted PA Hs with embedded helicene moieties. [228] Many reports of oxidatively synthesized helicenes soon followed-selected examples are shown in Figure 17.
Müllen, Narita, and co-workers reported that, instead of the expected perihexacene derivative,t he reaction of the tetranaphthyl-substituted precursor with DDQ/TfOH produced the double [7]helicene 202 in 74 %yield as amixture of diastereoisomers (a pair of twisted enantiomers and a meso form, Figure 17). [229] Such aregioselectivity of the cyclization is impressive,s ince [7]helicene moieties are even more strained than [5]helicenes.R ecently,a na nalogue of 202 with two [6]helicene parts has also been described by using oxidative coupling in the final step. [230] Moreover,M iao and co-workers described as imilar double helicene with aP AH skeleton regioisomeric to 202. [231] Itami and co-workers synthesized ad ouble [6]helicene 203 by the reaction of tetra(biphenyl)-substituted naphthalene with DDQ/TfOH in dichloroethane ( Figure 17). [232] Similar to 202,t he product was also obtained as am ixture of three diastereoisomers.A na nalogous reaction of at hiophene-based precursor with MoCl 5 in dichloromethane over 4 molecular sieves afforded the not fully cyclized tetrahelicene 204 instead of the expected double helicene. [233] The formation of 204 was kinetically controlled;upon heating, the propeller-like arrangement of its thiophene-containing wings underwent quantitative isomerization to the less-strained diastereoisomer with the wings alternately tilted "up" and "down" relative to the central naphthalene plane.Repeating the reaction with MoCl 5 at room temperature without the addition of molecular sieves led to the formation of the two remaining C aryl À C aryl bonds,thereby providing an analogue of 203 (double helicene) containing four chlorine atoms as aconsequence of the MoCl 5 -mediated chlorination. [234] Octa(4-tert-butylphenyl)biphenylene undergoes efficient oxidation with DDQ/MsOH to form the distorted PA H 205, which is based on a [ 7]helicene moiety with one fourmembered ring (Figure 17). [235] Interestingly,o ne twisted eight-membered ring was also formed in this reaction.
Ther emaining three compounds presented in Figure 17 (206)(207)(208)w ere all reported in 2018 and belong to the class known as "superhelicenes", aterm coined for unusually large Compound 206 was synthesized by Juxa nd co-workers using DDQ/TfOH to oxidatively close 13 new C aryl -C aryl bonds in one operation ( Figure 17). [236] 206 consists of two penta(tert-butyl-HBC) units fused to ac entral furan core, hence,forming an oxa [7]helicene derivative.Replacing DDQ by FeCl 3 as an oxidant leads to the non-fully cyclized bis-HBC ether (lacking the furan ring) which, however,readily cyclizes to 206 upon exposure to light.
CampaÇa and co-workers synthesized the superhelicene 207 in 7% yield by employing DDQ/TfOH as an oxidant ( Figure 17). [237] Thea uthors have also reported the synthesis of other large PA H-helicenes and superhelicenes by oxidative coupling. [238,239] Compounds 208 a, 208 b, [240] and larger analogues [241] reported by Wang and co-workers are amongst the most impressive examples of curved PA Hderivatives prepared by oxidative coupling (Figure 17). These propeller-shaped hexapole [7]helicenes based on aH BC core were obtained by oxidation of the corresponding dendrimer-like oligophenylene precursor with DDQ/MsOH, which resulted in the formation of 18 new C aryl -C aryl bonds in one step.T he enantiomers of 208 a were separated by HPLC on ac hiral phase and the helicity of the fractions was elucidated from direct observation with aSTM microscope. Figure 18 presents helicene-like compounds based on thiophene and pyrrole.B uu sing FeCl 3 as an oxidant, Aida and co-workers synthesized propeller-shaped molecules containing multiple thiophene rings,t hat is, 209 and its two C 3symmetric regioisomers. [242] Heterohelicene 210 was synthesized by Dehaen and coworkers as ad emonstrative application of the oxidative coupling conditions they had optimized for the synthesis of dithienyltriphenylene analogues. [243] Cyclization using DDQ or FeCl 3 was found to be much faster than photocyclization (1.5-2 hversus 72 hf or completion).
TheM üllen [245,246] and Jasti [247] research groups tried to apply intramolecular oxidative coupling in the synthesis of Figure 18. Heterocyclic helicene-likec ompounds. Cyclization conditions:a)FeCl 3 (6.6-12 equiv), CH 2 Cl 2 ,CH 3 NO 2 ,08 8C; b) DDQ (4.5 equiv), BF 3 ·Et 2 O, CH 2 Cl 2 ,08 8C; c) DDQ (5 equiv), Sc(OTf) 3 , toluene, reflux. segments of carbon nanotubes (so-called nanobelts);h owever,t heir attempts failed because of strain-relieving rearrangements.O nly very recently,C hi, Miao,a nd co-workers succeeded in the synthesis of the armchair and chiral carbon nanobelts 212 and 213,r espectively,u sing FeCl 3 or DDQ/ Sc(OTf) 3 as the oxidants (Figure 19). [248] This impressive achievement is ac rowning demonstration of the capabilities of the oxidative coupling method. Thes ame group has recently reported the preparation of at hiophene-based nanoring using FeCl 3 as the oxidant. [249] 4. Surface-Assisted (Cyclo)Dehydrogenation (CDH) In contrast to at ypical oxidative aromatic coupling reaction, as urface-assisted CDH process can be considered agreener alternative because this method generally produces aminimal amount of by-products and it does not require any solvent. An exemplary process of this type is the formation of tribenzo[a,g,m]coronene (215)f rom its molecular precursor 214 (Scheme 29). Research into the assembly of carbon-rich materials by an on-surface method was initiated by the synthesis of fullerene C 60 and its triaza-analogue, [250] hexabenzocoronene (138,R= H), [251] and other aromatic hemispheres [252] from compounds 138.S ince then, many challenging syntheses of carbon-based nanostructures have been realized by employing this approach, including single-chirality (that is,having one single chirality index (n,m)indicating the length and the direction of the circumventing vector) single-walled carbon nanotubes, [253] the longest to-date acenes [254] and periacenes, [255] PA Hs with embedded non-hexagonal rings, [256] and carbon-rich molecules with embedded nitrogen atoms. [169,250,257] An indisputable advantage of this method is the clear preference of the arene rings to undergo exclusively the desired cyclization that leads to the extended nanographenes and results in low-defect assemblies. Surface-assisted synthesis has been elegantly summarized in recent literature, [258][259][260][261] which is why we will only briefly describe the most important contributions to this field in the following section.
As ac onsequence of the excellent physicochemical properties of graphene,ag reat amount of effort has been made by researchers to prepare atomically precise graphene nanoribbons (GNRs). Theg eneral concept for the rational synthesis of such assemblies employing aC DH reaction usually includes two steps:1)anon-surface polymerization of ah alogenated small-molecule precursor by ah omolytic cleavage of the carbon-halogen bond after evaporation onto ac lean noble metal surface under an ultrahigh vacuum and 2) aCDH sequence at elevated temperature,which yields the fully conjugated nanoribbon structure.F ollowing this concept, many atomically precise GNRs have been prepared from the corresponding molecular precursors (Scheme 30; GNR 217, [263] 219, [264] 221, [265] 223, [266] 225, [267] 227, [268] 229, [269] and 231 [127] ). Thep hysicochemical properties of such GNRs may by altered not only by changing the size of the assemblies (Scheme 30 A), but also by doping with heteroatoms (Scheme 30 B) or changing the edge structure of the GNRs (Scheme 30 C).
As has been proved many times,the CDH process occurs typically between two arene rings in proximity.F asel, Müllen, and co-workers have found that, during the CDH process, methyl groups that are placed in proximity to aryl rings undergo oxidative cyclization with neighboring aromatic units. [270] Specifically,t he molecular precursor 232 undergoes polymerization followed by as eries of CDH processes to afford graphene nanoribbon 234 with azigzag edge topology (Scheme 31 A). This concept was further extended to dibromodimethylterphenyl 235 (Scheme 31 B), [271] where the polymerization/surface-assistedo xidative ring-closure sequence between am ethyl group and the neighboring aryl moiety gives rise to indenofluorene-based polymers 237 and 238.This strategy could eventually be employed in the preparation of graphene nanoribbons containing five-membered rings, because such am odification at specific positions can allow for the fine-tuning of electronic properties.A ccording to the same strategy,u ltra-low-gap open-shell molecules,s uch as peri-tetracene (240 from 239), ab enzenoid graphene fragment with az igzag edge topology,a nd dibenzo-[a,m]dicyclohepta[bcde,nopq]rubicene (242 from 241), anonbenzenoid nonalternant structural isomer of peri-tetracene with two embedded azulene units,w ere synthesized [272] by surface-assisted CDH (Scheme 31 C). Spin-polarized DFT calculations revealed that both compounds should exhibit an open-shell singlet ground state,t hus making them promising candidates for spintronic applications.
Thep ower of the CDH reaction has been recently highlighted by Fasel, Müllen, and co-workers (Scheme 32). [273] Atypical DDQ-mediated oxidative aromatic coupling performed on 243 leads to the propeller-shaped Scheme 29. The concept of asurface-assisted CDH process toward carbon-rich materials. [262] Reagents and conditions: a) Cu(111), ca. 230 8 8C. molecule 244.A lthough ac lassical oxidative aromatic coupling method was unsuccessful, the CDH process was accomplished on aA u(111) surface at elevated temperature, thus giving the nonplanar porous nanographene analogue 245.
Despite all the advantages described above,t he CDH method still has some limitations.Many functional groups are not stable to the elevated temperatures required and, thus,the possibility of derivatizing the structures prepared by CDH is rather limited. Moreover,t he synthesized nanographenic structures may also be unstable under CDH conditions.F or practical applications,l arge amounts of ag iven material should ideally be obtainable in ar elatively short amount of time;h owever, the CDH method does not yet fulfill this criterion.

Summary and Outlook
From small-molecule natural products and drugs,through fluorescent dyes and polycyclica romatic hydrocarbons to nanographenes,curved arenes,and nanobelts-the wealth of structures that can be synthesized by the oxidative coupling of arenes is tremendous.Enormous efforts by many researchers, from both theoretical and experimental standpoints,h as led to an improved understanding of oxidative coupling and provided definitive evidence for the two main mechanisms: via arenium and radical cation intermediates.S lowly,p redominantly thanks to the studies by the groups of Waldvogel, Müllen, and Pappo,weare approaching the point where it is possible to predict the reaction outcome before the reactants are even put into the flask;h owever,alot of research is still required to reach this goal.
Simultaneously to the mechanistic studies,s ignificant progress has been made in the development of new reagents and conditions,inparticular those enabling the more efficient and more selective intermolecular oxidative homo-and crosscoupling of arenes.T he most interesting of these include MoCl 3 [OCH(CF 3 ) 2 ] 2 ,( tBuO) 2 ,R h/C,a nd AgSO 4 .H owever, in many cases of cross-coupling alarge excess of one arene is still necessary to achieve good yields of heterobiaryls.T he synthetic possibilities have also been vastly expanded by the broader application of electrochemical methods.
In the meantime,the intramolecular oxidative coupling of arenes has revealed its full synthetic potential, which can be concluded from the vast number of different structures that have been synthesized in recent years.C ompared to the intermolecular version, the regioselectivity of intramolecular oxidative coupling is much easier to predict and plan. Moreover,m any of the structures that are accessible by intramolecular oxidative coupling,i np articular large planar and curved PA Hs,w ould be nearly impossible to synthesize using other methods for forming biaryl bonds because of the required prefunctionalization. Although avariety of valuable reactants are being developed for oxidative coupling, intramolecular oxidative coupling is dominated by two oxidants: FeCl 3 and DDQ/acid (Rathore conditions). These two reagents have been used by the Müllen, Itami, Miao,a nd Wu groups for the preparation of the most spectacular PA H molecules to date,i ncluding nanographenes,s uperhelicenes, Scheme 30. Selected examples for the on-surface synthesis of atomically precise graphene nanoribbons( GNRs) from small-molecule precursors. and nanobelts.I ti sa lso worth emphasizing that some very strained products,such as helicenes,bowls and saddles,can be synthesized using this method. Indeed, in contrast to earlier assumptions,the Scholl reaction is capable of proceeding even if ring closure is accompanied by the introduction of significant steric strain that leads to nonplanar molecules. [274,275] Progress has been particularly impressive in the case of surface-assisted dehydrogenation, which has enabled the synthesis of nanographenes of unprecedented size by scanning tunneling microscopy. [169,276] Despite all the impressive progress summarized herein, methods for the oxidative coupling of arenes still have some limitations,which will no doubt be the focus of future studies.