Synthesis of Heterocyclic [8]Circulenes and Related Structures

SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, A–AB A account

Syn lett T. Hensel et al. Account

Thomas Hensel Nicolaj N. Andersen Malene Plesner Michael Pittelkow*

Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark [email protected]

Received: 09.08.2015 1 Introduction Accepted after revision: 29.09.2015 Published online: DOI: 10.1055/s-0035-1560524; Art ID: st-2015-a0625-a [n]Circulenes (Figure 1) are fully conjugated polycyclic compounds that can formally be derived from the alicyclic Abstract In this account we give an overview of the synthesis and [n]radialenes by connecting the termini of the semicyclic properties of heterocyclic [8]circulenes. Much of the interest in study- double bonds by etheno bridges.1 Another way to view the ing heterocyclic [8]circulenes stems from the planar cyclooctatetraene core often contained in these compounds, which in principle is antiaro- [n]circulenes is as a class of compounds that are character- matic. We start with a short introduction to the hydrocarbon [n]circu- ized by having a central ring with [n] sides surrounded by a lenes and proceed to describe the synthetic chemistry involved in creat- band of ortho-fused benzene rings. ing tetraoxa[8]circulenes, with particular focus on the acid-mediated The largest [n]circulene that has been synthesized is oligomerization of benzo- or naphthoquinones, resulting in some simple rules for predicting the outcome of the oligomerization reactions. [8]circulene (6) as a π-extended derivative, and the largest These rules have guided the synthetic strategies for the preparation of [n]circulene that has been described computationally is azatrioxa[8]circulenes and diazadioxa[8]circulenes, which will be de- [20]circulene.1a As [3]radialene is known, one might expect scribed in separate sections of this account. More traditional synthetic that [3]circulene would exist as well, but so far the synthe- strategies have been applied in the preparation of octathia[8]circulene, sized [n]circulenes only span the bowl-shaped [4]circulene tetrathiatetraselena[8]circulene, and a number of other heterocyclic [8]circulenes, and these synthetic efforts will be highlighted. Finally, a 2 and [5]circulene 3, the planar [6]circulene 4 and the sad- section describing structures that are closely related to the heterocyclic dle-shaped [7]circulene 5 and [8]circulene 6 (Figure 1). In a

[8]circulenes will be presented, and at the end we will comment on the computational study, Hopf and co-workers predicted the Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. extensive theoretical work regarding the question of aromaticity/anti- geometries of all hydrocarbon [n]circulenes from the [3]cir- aromaticity of the central cyclooctatetraene of heterocyclic[8]circu- culene 1 to [20]circulene.1a They described the strain ener- lenes. 1 Introduction gy associated with enlarging the [n]circulene structure as 2 Synthesis of [n]circulenes compared to the energy associated with [6]circulene 4. The 2.1 [4]Circulene larger structures become helical, as predicted by density 2.2 [5]Circulene functional theory (DFT) calculations. The existence of a 2.3 [6]Circulene [3]circulene is considered unfeasible. 2.4 [7]Circulene 2.5 [8]Circulene Heterocyclic circulenes are [n]circulenes where one or 3 Synthesis of Tetraoxa[8]circulenes: A Historical Perspective more of the etheno bridge(s) have been replaced with a he- 4 Synthesis of Azatrioxa[8]circulenes teroatom such as oxygen, sulfur, nitrogen, or selenium. 5 Synthesis of Diazadioxa[8]circulenes Some of the known hetero[8]circulenes (substituents not 6 Synthesis of Other Heterocyclic [8]Circulenes 7 Synthesis of Structurally Related Compounds shown) are presented in Figure 2. The slightly different ge- 8 Hetero[8]circulenes and Related Compounds as Tools to Study ometries of furan, thiophene, pyrrole, and other five-mem- Aromaticity and Antiaromaticity bered 6π-aromatic systems as compared to benzene make 9 Conclusion and Outlook the heterocyclic [8]circulenes very different from hydrocarbon [8]circulenes, both in their geometry and chemical and Key words circulenes, heterocycles, aromaticity, antiaromatcity, synthesis, geometry, cyclooctatetraenes, nucleus-independent shifts physical properties. The relationship between the structures of circulenes and the geometries of these compounds

Syn lett T. Hensel et al. Account has attracted significant interest.1 The emergence of non- whether the circulene is planar or bowl-shaped as shown in planar, fully conjugated systems, such as the fullerenes and Figure 3. We believe that Dopper and Wynberg’s model falls carbon nanotubes, has certainly served as an inspiration for short in its ability to predict saddle-shaped circulenes, as it studies of the fundamental properties of non-planar circu- can be difficult to define an outer radius of a saddle. We lenes.2 In an early study, Dopper and Wynberg introduced a therefore propose an alternative model in which the wedge simple yet efficient approach for analyzing the geometry of angles of the aromatic moieties are summed, as shown in circulenes using a mathematical model containing the in- Figure 4. This model was inspired by considerations from 4 ner (r1) and outer (r2) radii of the circulene, and the length Högberg’s doctoral thesis. The wedge angles are derived of the spokes (a).3 From this model, it is possible to assess from literature DFT calculations5 using the C–C–C bonding quickly, without the need of computational modelling, angle of the cyclic compounds. Comparing the sum of the

Biographical Sketches

Thomas Hensel received his gree was carried out in Michael the Department of Chemistry, M.Sc. degree from Leipzig Uni- Pittelkow’s group at the Univer- University of Copenhagen, versity in 2012. Supported by sity of Copenhagen. He is cur- working on the synthesis and the Erasmus program, the prac- rently a Ph.D. student under the applications of novel hetero- tical work of the master’s de- direction of Michael Pittelkow at [8]circulenes.

Nicolaj Nylandsted Anders- pervision of Michael Pittelkow. tin[6]urils, again under the en was born in 1991 on the is- During his bachelor’s and mas- supervision of Michael Pittel- land of Funen, Denmark. He ter’s studies, he has been devel- kow. He was a recipient of the completed his B.Sc. in 2013 and oping helicene chemistry with Novo Scholarship Programme in his M.Sc. in 2015 at the Depart- possible applications in DNA 2014. ment of Chemistry, University recognition. He is currently pur- of Copenhagen under the su- suing a Ph.D., working with bio-

Malene Plesner was born in John Nielsen. In 2014, she com- tion of different azatrioxa[8]cir- Copenhagen in 1989. She stud- pleted her M.Sc. degree super- culenes. She is currently Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. ied chemistry at the University vised by Michael Pittelkow teaching high school chemistry of Copenhagen and received within the field of synthetic or- at Johannesskolen, Copenha- her B.Sc. degree in 2012 under ganic chemistry, focusing on gen. the supervision of Professor the synthesis and characteriza-

Michael Pittelkow was born Australia (CSIRO in Melbourne, Professor Jeremy K. M. Sanders in Brøndby Strand, near Copen- with Dr. Kevin Winzenberg), The before moving back to the Uni- hagen. He studied chemistry at Netherlands (The Technical Uni- versity of Copenhagen. In 2013, the University of Copenhagen versity of Eindhoven, with Pro- he became an associate profes- where he received his Ph.D. de- fessor E. W. Meijer) and the U.K. sor. His research interests in- gree in 2006 under the supervi- (University of Cambridge). He clude organic synthesis, sion of Associate Professor Jørn undertook postdoctoral train- physical organic chemistry, dy- B. Christensen. During his stud- ing at the University of Cam- namic combinatorial chemistry ies he spent extended periods in bridge under the mentorship of and supramolecular chemistry.

Syn lett T. Hensel et al. Account

wedge angles, Σ∠, one intuitively expects circulenes with Σ∠ S S Se Se S S values close to 360° to be planar, whereas lower Σ∠ indicate bowls and higher Σ∠ saddles. S S S S

(a) Se Se S S S S

6 7 8 [8]circulene tetrathiatetraselena[8] octathia[8]

S Se O

radialene scaffold band of ortho-fused with etheno bridges benzene rings S S Se Se O O

(b) S Se O

9 10 11 tetrathia[8] tetraseleno[8] tetraoxa[8] 12 3 H H [3]circulene [4]circulene [5]circulene N N unknown derivate known corannulene bowl-shaped known bowl-shaped O O O O

O N H 12 13 14 azatrioxa[8] diazadioxa[8] tetramethano[8]

45 6 Figure 2 Structures of synthetically available heterocyclic [8]circu- [6]circulene [7]circulene [8]circulene lenes. The core structures are shown without substituents coronene known derivative known known saddle-shaped saddle-shaped planar scription of the synthetic work developed for the syntheses Figure 1 Structures of [n]circulenes. (a) [n]Circulenes may be viewed as derivatives of [n]radialenes or as rings of ortho-fused benzene rings. of heterocyclic [8]circulenes. We will devote special em- (b) Geometries of [n]circulenes phasis on the early work developed by Erdtman and Hög- berg on the preparation of tetraoxa[8]circulenes and how the mindset developed in their work has inspired our syn- By comparing 15 circulenes,3,6 we found that planar cir- theses of azatrioxa- and diazadioxa[8]circulenes. We will culenes indeed reside in a narrow interval between 336° also describe the synthetic efforts in developing other types and 380°. An exception is tetrathia[8]circulene 9 at 420°. of heterocyclic [8]circulenes ranging from the parent octa-

The bond angles of the thiophene moieties of this circulene thia[8]circulene 8 to tetraaza[8]circulenes embedded in Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. deviate significantly from those found in thiophene itself, large π-extended porphyrin arrays. Finally, we will focus on indicating that the elasticity of the thiophene moiety facili- a range of compounds that are related to heterocyclic [8]cir- tates the formation of a planar heterocyclic [8]circulene. culenes, in that they contain a planar cyclooctatetraene The transition to the helical geometry discussed computa- (COT) structure, and we will discuss the antiaromatic char- tionally by Hopf occurred at Σ∠ around 1000°, with a transi- acter of this moiety. tion from saddle-shaped [16]circulene (Σ∠ 960°) to helical 1a [17]circulene (Σ∠ 1020°). The lack of compounds does, however, make this geometry speculative for now, and syn- thesizing the strained helical structures will surely be a challenge. We are looking forward to seeing new circulenes being synthesized and characterized structurally to further validate our model. We especially welcome entries which can fill the gap between [5]- and [6]circulene so that the Figure 3 Dopper and Wynberg’s model. The geometry is estimated using the inner radius (r ), outer radius (r ), and length of the spokes (a) limit of Σ∠ between bowl-shaped and planar circulenes can 1 2 be determined more precisely. In this account we will brief- ly describe the seminal work on the syntheses of all-hydrocarbon [n]circulenes as well as a more comprehensive de-

Syn lett T. Hensel et al. Account

2.1 [4]Circulene

[4]Circulene 2 (quadrannulene) is, to date, the smallest [n]circulene, and was prepared as a π-extended derivative by King and co-workers in 2010.6e,7

Figure 5 X-ray crystal structures of [n]circulenes. (a) A [4]circulene derivative. (b) [5]Circulene. (c) [6]Circulene. (d) [7]Circulene. (e) An [8]circulene derivative. (X-ray crystal data are from the Cambridge Structural Database)

Hopf and co-workers have outlined different possible synthetic strategies toward the preparation of [4]circulenes.1a The King group used one of the Hopf strategies in their synthesis of a π-extended [4]circulene derivative (18).7 Although the yield of the synthesis reported was not impressive, the elegance of the synthetic route was remark- able. The [4]circulene 18 is obtained in only five steps via a final cobalt-mediated cyclotrimerization (Scheme 1).

R Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material.

TMS HO OH Figure 4 A model for estimating the geometry of circulenes based on O O n-BuLi 1. TsOH R R heterocyclic moieties. (a) Wedge angles of common aromatic rings and CeCl3 toluene, reflux cyclopentadiene. (b) Visual interpretation of circulene geometry using THF 2. KOH –78 to 25 °C R R MeOH, 25 °C the wedge angles to form Σ∠. (c) Spectrum of Σ∠ values of known circu- O O 50% lenes and their corresponding geometries. The circulene suffix has been HO OH 30% omitted for clarity

15 16

TMS 2 Synthesis of [n]Circulenes 1. CpCo(CH2CH2)2 TMS TMS TMS dimethoxyethane The crystal structures of [4]- to [8]circulenes are depict- 25 °C 2. Cp FePF ed in Figure 5. Only [5]-, [6]-, and [7]circulene have been 2 6 synthesized without substituents. 2% TMS TMS

17 18 Scheme 1 Synthesis of a quadrannulene derivative by King and co- workers

Syn lett T. Hensel et al. Account

The crystal structure of the [4]circulene 18 supported The final steps of the synthesis by Scholl and Meyer can the bowl predicted by Hopf. Though [4]- and [5]circulene be seen in Scheme 3a.10 In their approach, the dibenzocoro- are both bowl-shaped, the bowl inversion barrier of the two nene 22 was synthesized followed by oxidation with nitric are quite different, with [4]circulene being at a staggering acid to give first the dibenzocoronene quinone 23 and then 120 kcal mol–1 compared to that of [5]circulene at 9 kcal the coronene tetracarboxylic acid 24. In the final step, the mol–1, thereby showing the rigid nature of the product.1a coronene tetracarboxylic acid 24 was heated to 500 °C in the presence of calcium hydroxide to give the coronene 4. 2.2 [5]Circulene Other approaches for the synthesis of [6]circulene have been developed including one utilizing a ruthenium-cata- [5]Circulene 3 (corannulene) is the second lowest [n]cir- lyzed benzannulation (Scheme 3b).12 The high stability of culene. The synthesis of [5]circulene was first reported by coronene is reflected by the fact that it exists in Nature as Barth and Lawton in 1966.8 Their strategy was to build the the mineral carpathite.13 [5]circulene one ring at a time starting from an ester-substituted phenanthrene (Scheme 2a). In the final step, an (a) O HO2C CO2H aromatization over palladium-on-carbon gave the corannulene. The amount of steps in this synthesis was overwhelm- HNO3 ing. In 1991, a more viable synthesis using a different ap- 220 °C proach was reported by Scott et al.6j Their approach was to use flash vacuum pyrolysis to form [5]circulene directly from a substituted flouranthene 21 (Scheme 2b). HO CCOH Extensive research on the synthesis and properties of O 2 2 22 23 24 corannulene and several synthetic procedures have since NaOH 9 been reported. Much of the work appears to have been Ca(OH)2 500 °C driven by the fact that [5]circulene may be viewed as a frag- (b) O ment of the spherical C60 molecule. The bowl-shape of [Ru] [5]circulene and its resemblance to the fullerenes also NH4PF6 makes it an attractive starting point for the synthesis of larger fragments of the fullerenes and even for the synthe- O sis of carbon nanotubes.6j 25 26 4 Scheme 3 Synthesis of [6]circulene. (a) First reported synthesis by (a) OH O Scholl and Meyer. (b) Ruthenium-catalyzed benzannulation reported by O Shen et al.

2.4 [7]Circulene 19 20

[7]Circulene 5 (pleiadannulene) is saddle-shaped and Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. (b) 6k Pd/C was first synthesized in 1983 by Yamamoto et al. Their

flash vacuum synthetic approach was to first close the central seven- pyrolysis membered ring followed by the formation of the final benzene ring to complete the [7]circulene (Scheme 4a). The [7]circulene was crystallized, from which the saddle- 14 21 3 shaped geometry was confirmed. In 1996, a different synthetic method was described.15 Here the formation of both Scheme 2 Synthesis of corannulene. (a) First reported synthesis by Barth and Lawton. (b) Flash vacuum pyrolysis approach reported by the central ring and the peripheral ring was accomplished Scott et al. in a single step using flash vacuum pyrolysis. Finally, the saturated positions were dehydrogenated using palladium- on-carbon to give the fully unsaturated [7]circulene 2.3 [6]Circulene (Scheme 4b).

[6]Circulene 4 (coronene) was the first hydrocarbon cir- 2.5 [8]Circulene culene to be synthesized.10 While [5]circulene may be viewed as a fragment of the fullerenes, [6]circulene may be The syntheses of [8]circulene derivatives have very re- regarded as being a fragment of graphene.11 cently been reported by three different groups.6d,16 The strain inherent to the [8]circulene has been a possible hin-

Syn lett T. Hensel et al. Account

O O (a) Br Br O O (b) Br Br flash S 1. n-BuLi LiAlH4 Pd/C vacuum hν 2. DMF TiCl4 280 °C pyrolysis

27 28 29 5 32 31 30 Scheme 4 Synthesis of [7]circulene. (a) First reported synthesis by Yamamoto et al. (b) Flash vacuum pyrolysis approach

(a) Ar (b) N Ar PdOAc, NaOAc Ar Cl I I Ar Cl Cl n-Bu NCl Ar N 4 100 °C DMF Ar + + O S Pd(PPh3)3Cl2 110 °C Ar DMA

I I Cl Cl Cl MW Ar Ar

33 34 35 36 37 38 39 Scheme 5 Synthesis of [8]circulene derivatives. (a) Using a palladium-catalyzed cross-coupling approach. (b) Using a Diels–Alder reaction and a palladium-catalyzed cross-coupling approach drance for the synthesis of this particular [n]circulene. The compared to substituted derivatives.20a This was attributed first reported synthesis uses palladium-catalyzed annula- to the competition of mesomeric polarization on the qui- tions to give the [8]circulene derivative 35 in a single step noid core by the two carbonyl groups: the core had a dif- (Scheme 5a).6d The second combines two molecules by a fuse cationic character, and as such was not prone to regio- Diels–Alder reaction. Subsequently, the intermediate 38 is specific nucleophilic attack. 2-Methoxy-1,4-benzoquinone closed using a palladium-catalyzed cross-coupling to yield (41) acted differently: the symmetry of this system had the [8]circulene derivative 39 (Scheme 5b).16a been disrupted, and the carbonyl group at the position 4 now had its electron demand satisfied by donation from the methoxy substituent. This makes the 5,6 double bond po- 3 Synthesis of Tetraoxa[8]circulenes: A His- larized, mainly due to the carbonyl group at position 1, torical Perspective leading to reaction in a Michael fashion in the Thiele acetylation (Scheme 7). The scheme also depicts the reaction Tetraoxa[8]circulenes 11 can be prepared from 1,4-ben- product of 2-methoxy-5-methyl-1,4-benzoquinone (43). zoquinones in yields that depend on the substitution pat- The reactive 5-position had been blocked, but having the tern of the 1,4-benzoquinone (Scheme 6). Dihydroxydiben- same carbonyl group dictate reactivity, the reaction occurs zofuran (40) was found to be an important intermediate in at position 3, although slower than in the former example. the transformation.17 O isolated OAc Michael O MeO 1 MeO

system Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. O 6 Ac2O O 5 carbonyl electron OAc demand satisfied 4 O O by OMe donation O OAc 41 42 HO OH O O O OAc 11 40 MeO MeO Ac2O

Scheme 6 Retrosynthetic analysis of tetraoxa[8]circulene 3 AcO O OAc 18 It was first observed by von Knapp and Schultz in 43 44 19 1881, and Liebermann in 1885, that mixing 1,4-naphtho- Scheme 7 Regioselectivity of the Thiele acetylation of benzoquinones quinones under acidic conditions led to an insoluble oligo- as discussed by Erdtman. The positions discussed in the text have been merization product. The work connecting the discoveries of numbered the 19th century with modern day tetraoxa[8]circulene chemistry is outlined in this section. Erdtman described his In addition to the two-electron mechanisms described work on quinone reactivity in a series of publications in above, radical coupling of quinones was also investigated by 1933.20 The reactivity and stability of substituted benzoqui- Erdtman:20b the possibility of isomerization between oxy- nones were examined with the foundation of the work be- gen and carbon radicals for phenols was discussed based on ing the high stability of unsubstituted 1,4-benzoquinone literature reports by Pummerer, with prediction of reactivi-

Syn lett T. Hensel et al. Account

ty at ortho- and para-positions.21 In the oxidative coupling elimination of benzoquinone, the regioselectivity was predicted based on the Michael addition model and confirmed experimen- t-Bu OH t-Bu t-Bu t-Bu tally. The reactivities of 2-substituted benzoquinones fol- O O lowed the same trend as for Thiele acetylation: HO > MeO >

Me > H (Scheme 8). The subsequent formation of furan MeO O MeO OH rings was analyzed20c,d with the proposed mechanism de- 51 52 picted in Scheme 9. The same trend in reactivity as for the benzoquinone couplings was observed. For 2-methyl-1,4- reduction and condensation benzoquinone, a product of condensation 48 was observed Scheme 10 Overview of the synthetic structure elucidation performed that contained two phenolic and two furanic oxygen atoms. by Hewgill and Kennedy It was suggested that the reduced reactivity of the methyl R R derivative facilitates new reaction pathways to yield a ter- O R Yield molecular product, with the proposed structure shown in O R R AlCl 11: H 0.2% R 3 Figure 6. The formation of the furan rings from 2-methyl- NO2Ph 53: Me 60% O 54: Pr 60% 1,4-benzoquinone had to occur with nucleophilic attack on O R 55: 40% the carbonyl groups in order to arrive at the proposed O R R 50: 95% structure. Also depicted in Figure 6 is the proposed struc- O R R ture of the product of condensation of naphthoquinone, the tribenzotrioxa[6]circulene 49. This trimeric structure was Scheme 11 Formation of tetraoxa[8]circulene from 2,3-disubstituted 1,4-benzoquinones. Increasing 2,3-disubstitution increases the yield of retracted and the tetrameric structure 50 was proposed the reaction based on mass spectrometry in a publication from 1968.22 Disregarding the incorrect structure elucidation, this was nevertheless the first report of a tetraoxa[8]circulene. In 1966, Hewgill and Kennedy further examined intermediates in the formation of dibenzofurans from benzoqui- O HO OH nones.23 The structure of the intermediate hemiacetal 51 R acid was confirmed both with NMR spectroscopy and by two R R transformations converging at the monohydroxy com- O O O pound 52, as shown in Scheme 10. 45 Erdtman and Högberg reported on a whole series of 24 Scheme 8 Reactivity of benzoquinones in a dimerization reaction. R: tetraoxa[8]circulenes in 1970. 2,3-Disubstitution at the OH, OMe, Me, or H 1,4-benzoquinone led to increased yields (Scheme 11), and the authors stated that the circulenes might be formed by O two competing pathways, that is, by sequential addition of MeO O monomers or by combination of two dimers. O O MeO OMe Following his collaboration with Erdtman, Högberg re-

leased a series of papers entitled ‘Cyclo-oligomerizations of Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. O OH 17,24b,25 OMe O Quinones’, beginning in 1972. He noticed that adding O dihydroxydibenzofuran 40 increased the yield of tetra- 46 47 oxa[8]circulene, further indicating that this was indeed an Scheme 9 Formation of furan rings as investigated by Erdtman intermediate of the reactions. In addition, a conclusion was reached that 2,3-disubstitution was favored over 2-mono- substitution in the formation of circulenes, in accordance O with the quinone couplings seen by Erdtman in 1933. Hög- O O berg also showed that it was possible to create mixed di- O O mers, trimers and circulenes from resorcinol, naphthoqui- O O none, and benzoquinone. The resorcinol acted as a termina-

OH HO tor, preventing further oligomerization due to the lack of O O ortho or para relationships between substituents. 48 49 50 In 1977, Erdtman joined Högberg again, collaborating Figure 6 Structures from the work of Erdtman. Compound 48: struc- on providing crystal structures of the dihydroxydibenzofu- ture of the product obtained from condensation of 2-methyl-1,4-ben- ran 40 and the trimer and open tetramer of benzoqui- zoquinone. Compound 49: proposed structure of the product of the none,26 giving some concluding remarks on the mechanistic condensation of naphthoquinone. Compound 50: corrected structure aspect of the formation of circulenes.27 They observed that of the tetrameric condensation product adding a strong oxidant, chloranil, inhibited the reaction,

Syn lett T. Hensel et al. Account

OMe OMe H2/PtO2 OMe BF3OEt2 R R (NH4)2Ce(NO3)6 O Li R' AcOH/AcOEt CH2Cl2 O R' R MeCN/H O Br THF Δ 2 R Δ R R Br 58–78% 22–90% 59–98% 11–56% R' R R O O OMe OMe OMe O

56 57a–e 58a–e 59a–e R R O R R

60a–e Scheme 12 Synthesis of octaalkylated tetraoxa[8]circulenes. R′ = n-butyl to n-octyl. R = n-heptyl to n-undecyl indicating that hydroquinone was needed for the reaction Both [8]circulenes were submitted to optical and electro- to proceed, and suggesting a hemiketal intermediate in the chemical spectroscopy and were oxidized to form stable reaction and a non-radical mechanism. radical-cation salts. Some of the first well-soluble tetraoxa[8]circulenes, In 2010, Christensen and Pittelkow constructed organic synthesized with liquid crystallinity in mind, were de- light-emitting diodes (OLEDs) using tetraoxa[8]circu- scribed by Christensen and co-workers in 2000.28 Alkyl lenes.31 The compounds discussed in their paper (50 and chains of different length (C7 to C11) on the benzene moi- 66–70) were produced in a statistical condensation of 1,4- eties were achieved by reaction with an alkynyllithium naphthoquinone and 2,3-undecyl-1,4-benzoquinone with compound on a bis-bromomethyl compound 56, followed boron trifluoride–diethyl ether complex in boiling di- by reduction of the triple bond with hydrogen/platinum(IV) chloromethane (Scheme 14). A tetraundecyldinaphthocir- oxide (H2/PtO2), yielding 2,3-dialkyl-1,4-dimethoxyben- culene with trans-configuration of the substituents was zenes 58a–e (Scheme 12). After oxidation with cerium(IV) found to have a quantum yield of 0.83, and the octaunde- ammonium nitrate,29 the 2,3-dialkyl-1,4-benzoquinones cylcirculene was found to emit blue light, which is valuable 59a–e were reacted with boron trifluoride–diethyl ether in the development of OLEDs. complex (BF3·OEt2) in boiling dichloromethane to give dif- In another publication by our group, the unusual aggre- ferently alkylated tetraoxa[8]circulenes 60a–e. gation behavior of different regioisomers of tetra-tert-but- There were two distinct phase transitions observed in yltetraoxa[8]circulene 71–74 was examined (Scheme 15).32 the substances with heptyl, octyl, nonyl or decyl chains, A condensation reaction of four 2-tert-butyl-1,4-benzoqui- with increasing chain length lowering both the transition nones with boron trifluoride–diethyl ether complex in di- temperatures. These compounds also showed other physi- chloromethane yielded all four regioisomers. The com- cal properties associated with liquid crystallinity, such as pounds were highly soluble in dichloromethane and hep- birefringence (dependence of the refractive index on the tane. polarization and direction of propagation of light) and The four-fold symmetrical tetraoxa[8]circulene 71 was shearability (deformation of the liquid crystal after apply- isolated from the mixture by dry column flash chromatog-

ing a unidirectional force). This was in contrast to an octa- raphy, and product 72 was crystallized from the remaining Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. propyl derivative (prepared from 2,3-dipropylbenzoqui- mixture. Figure 7 depicts the herringbone crystal packing none), which did not show liquid crystallinity.28 of 71.

Efforts by Rathore and co-workers resulted in bicyc- The reaction of 71 with aluminum chloride (AlCl3) in lo[2.2.2]octane- and bicyclo[2.2.1]heptane-annulated tetra- boiling benzene enabled us to produce the insoluble tetraoxa[8]circulene derivatives.30 The synthetic pathway lead- oxa[8]circulene 11 in quantitative yield (Scheme 16). A re- ing to compounds 65a and 65b is depicted in Scheme 13. cent member of the tetraoxa[8]circulene family was syn-

R R R O O O OAc OAc O BF3⋅OEt2 1. HCl/EtOH Ac2O Pd/C, H2 CH2Cl2 EtOH Py EtOH 2. NO2/O2 Δ R R R R O O a: 70% b: 76% O O OAc OAc O 61a,b 62a,b 63a,b 64a,b R O R

65a,b

Scheme 13 Synthesis of bicyclo-annulated tetraoxa[8]circulenes. a: R = –CH2–; b: R = –CH2CH2–

Syn lett T. Hensel et al. Account

O O R BF3O⋅Et2 C11H23 CH2Cl2, Δ

C11H23 O O R R R O O R R R

O O O O

R R R R O O R R R R 66 67 Figure 7 X-ray crystal structure of regioisomer 71

R O O R thesized in 2014 by Christensen.6a The geminally dialkylated tetraindanotetraoxa[8]circulene 82 was devised and O O O O synthesized with a possible application as a discotic liquid

R R R crystal system in mind. The synthetic pathway had 2,5-di- O O methoxybenzaldehyde (75) as a starting material, yielding R R R 68 69 4,7-dimethoxy-2,3-dihydro-1H-inden-1-one (81) after six steps. Condensation using boron trifluoride–diethyl ether

O O complex in dichloromethane gave the tetraoxa[8]circulene 82 (Scheme 17). However, the product did not show any mesophase by differential scanning calorimetry (DSC). O O O O t-Bu R O O AlCl O O t-Bu 3 R benzene Δ 70 50 O O O O 99% Scheme 14 Condensations of 1,4-quinones. The product mixture is composed of all the possible regioisomers t-Bu O O t-Bu 71 11 O Scheme 16 De-tert-butylation producing the unsubstituted tetra- BF3⋅OEt2 t-Bu CH2Cl2 oxa[8]circulene 11

50% Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material.

t-Bu O 4 Synthesis of Azatrioxa[8]circulenes O O t-Bu t-Bu t-Bu The previous section addressed Högberg’s and Erdt- O O O O man’s work on the acid-mediated condensations of 1,4- benzo- and 1,4-naphthoquinones. They observed different t-Bu linear phenolic and furanic structures and concluded that O O t-Bu t-Bu t-Bu 3,6-dihydroxydibenzofuran was an important intermediate 71 72 (Scheme 6).27 Derived from these results, we set out to syn- thesize azatrioxa[8]circulenes using dihydroxycarbazole as t-Bu t-Bu O O an analogue of dihydroxydibenzofuran (Scheme 18). A few t-Bu t-Bu challenges arose from using 9H-carbazole: both positions α to the hydroxy groups are reactive toward coupling with O O O O 1,4-benzoquinone. The resulting non-regioselective oxida-

t-Bu tive coupling would yield regioisomers. Allowing only reac- O O tivity at the 4- and 5-positions required blocking the 2- and t-Bu t-Bu t-Bu 7-positions, preferably using bulky protecting groups that 73 74 would also increase the solubility of the compounds by pre- Scheme 15 Synthesis of tetra-tert-butyltetraoxa[8]circulenes 71–74 venting aggregation between the large π-systems. In the

Syn lett T. Hensel et al. Account

CH (CO H) R'' OMe 2 2 2 OMe R R Py O N CHO piperidine CO2H H2, Pd/C R R R' R' 92% 98% O O O O OMe OMe 75 76 R R R R O O R R R R OMe OMe R–I 1. SOCl2 83 85 NaH CO2H DMF (cat.) 2. AlCl3 THF 72% 52–65% O transfer OMe OMe R'' R R of synthetic 77 78 O 8 N 1 logic 9 R R R' 7 2 R'

H (3.8 bar) 6 3 2 HO OH HO 5 4 OH OMe Pd/C OMe AcOH (NH4)2Ce(NO3)6 84 86 R HClO4 (cat.) R MeCN/H2O + R 81–87% R 92–96% O OMe OMe O 79 80 O R R

R R R R R R O O O O BF3·OEt2 Scheme 18 Retrosyntheses of tetraoxa[8]circulene 83 and azatri- R CH2Cl2 O O oxa[8]circulene 85. Numbering of the carbazole positions is shown R 13–26%

O 81 O zyl- or N-propylcarbazole was then brominated at the 3- R R R R and 6-positions. In the subsequent step, the dibromo com- 82 pounds 88a,b were transformed into dimethoxycarbazoles Scheme 17 Synthesis of a geminally dialkylated tetraindanotetra- 89a,b, which underwent Friedel–Crafts tert-butylation to oxa[8]circulene 82 block the 2- and 7-positions, thereby increasing the solubil- ities of the products. The N-propyl-2,7-di-tert-butyl-3,6-di- methoxycarbazole 90a was demethylated with boron 33 work with tetraoxa[8]circulenes, we had previously shown tribromide (BBr3) in dichloromethane. Boron tribromide that tert-butyl groups were desirable for guiding the reac- proved inefficient in the demethylation of N-benzylcarba- tivity and achieving high solubility in organic solvents. An- zole 90b, as the benzyl group was also cleaved resulting in

other reactive center, the carbazole nitrogen, needed pro- an oxidation-sensitive compound. Increased reaction times Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. tection from undesired reactions. On the basis of these re- for the demethylation led to cleavage of the tert-butyl quirements, the formation of azatrioxa[8]circulenes from groups. Various attempts using, for example, AlCl3, lithium reactions of a suitably substituted 3,6-dihydroxy-9H-carba- iodide (LiI), sodium 1-butanethiolate (NaSBu) or sodium zole with 1,4-benzoquinones or 1,4-naphthoquinone was benzeneselenolate (PhSeNa) did not yield the desired prod- investigated. The presence of tert-butyl groups at the 2- and uct 92. Only adding an excess of boron trichloride in combi-

7-positions prevented polymerization, driving the reaction nation with tetra-n-butylammonium iodide (n-Bu4NI) and toward the cyclic product. A benzyl group was chosen for shortened reaction times produced N-benzyl-2,7-di-tert- the protection of the nitrogen at the 9-position based on its butyl-3,6-dihydroxycarbazole (92), selectively. All the reac- stability and many means of deprotection. Different alkyl tions proceeded with high yields and the products were pu- chains were also employed for blocking the nitrogen. It was rified by either crystallization or trituration, with the ex- important to utilize a 1,4-quinone with substituents at ei- ception of the demethylation step, where column chroma- ther the 2-position or both the 2- and 3-positions in order tography was necessary.6b,34 to avoid unwanted condensation products, as experienced The N-substituted 3,6-dihydroxycarbazoles 91 and 92 by Erdtman and Högberg.4,17,22,24–27 The synthetic pathway are important intermediates in the advancement of all of starting from 9H-carbazole yielding N-substituted 2,7-di- our subsequent work with azatrioxa[8]circulenes and di- tert-butyl-3,6-dihydroxycarbazoles 91 and 92 is presented azadioxa[8]circulenes. They can be readily condensed with in Scheme 19.6b The 9H-carbazole was protected with a electron-rich 1,4-benzoquinones and 1,4-naphthoquinone benzyl or propyl group by phase-transfer catalysis. N-Ben- to form asymmetrical and symmetrical azatrioxa[8]circu-

Syn lett T. Hensel et al. Account

a: PrBr, b: BnBr R 1. O 2. O R H R' R'' N n-Bu4NI, toluene N N 12 M NaOH t-Bu t-Bu a: 96% O O b: 98% O O 87a,b R' and R'': EDG

NaOMe/MeOH R CuI Br2 R O AcOH N DMF R'' R' Δ N 93 t-Bu t-Bu a: 98% a: 94% b: 95% Br Br b: 88% R HO OH 88a,b 91 or 92 N t-Bu t-Bu R R FeCl3 N t-BuCl N O R''' O O CH2Cl2 t-Bu t-Bu a: 73% O b: 75% MeO OMe MeO OMe O 89a,b 90a,b R''': EDG R''' R''' 94

R Scheme 20 Synthesis of unsymmetrical azatrioxa[8]circulenes 93 and a: BBr3, CH2Cl2 34 b: BCl3, n-Bu4NI, CH2Cl2 N symmetrical azatrioxa[8]circulenes 94. 91: R = propyl. 92: R = benzyl t-Bu t-Bu 91: 86% 92: 85% HO OH addition, which causes the dihydroxycarbazole to dimerize, 91, 92 forming diazadioxa[8]circulene 104. This dimerization re- Scheme 19 Synthesis of N-substituted 2,7-di-tert-butyl-3,6-dihydroxy- action is described in section 5. After further treatment carbazoles 91 (R = propyl) and 92 (R = benzyl). a: R = propyl. b: R = benzyl6b with a Lewis acid and an oxidizing agent (chloranil), a furan ring (structure 96) is formed from the condensation of two phenols, presumably via a quinoid intermediate. Addition lenes 93 and 94 as presented in Scheme 20.34 We have of a second 1,4-quinone in the presence of boron trifluo- shown that the azatrioxa[8]circulene is formed in a step- ride–diethyl ether complex yields an azatrioxa[8]circulene wise fashion, where two intermediates could be isolated 93. The second 1,4-quinone may be different to the one al- (Scheme 21). On treating 3,6-dihydroxycarbazole 92 with ready attached, resulting in an unsymmetrical azatri- one equivalent of an electron-rich 1,4-benzoquinone (or oxa[8]circulene. This cyclic trimerization reaction of 3,6-di- 1,4-naphthoquinone), and boron trifluoride–diethyl ether hydroxycarbazole 91 and two 1,4-quinones can be carried complex, one carbon–carbon bond is formed. We presume out in a stepwise manner with isolation of the intermedi- that the coupling takes place via a Michael-type addition. If ates, or in one-pot, to afford similar yields. In total, three an electron-poor 1,4-benzoquinone (Cl, Br, CN) is used, oxi- new carbon–carbon bonds and three furan rings are dation of the dihydroxycarbazole is preferred over Michael formed, releasing three molecules of water.6b,34

R R Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. N N t-Bu t-Bu t-Bu t-Bu

O O O O

O O t-Bu t-Bu

97 98

Bn Bn Bn N N N t-Bu t-Bu t-Bu t-Bu t-Bu t-Bu

O O O O O O

O O O t-Bu OMe t-Bu SC12H25 t-Bu 99 100 101 Figure 8 Azatrioxa[8]circulenes synthesized by Pittelkow and co-workers in 2015

Syn lett T. Hensel et al. Account

O O R Cl Cl N R' t-Bu t-Bu Cl Cl R O HO OH N O OH t-Bu t-Bu BF ·OEt BF3·OEt2 3 2 HO

HO OH R'

92 95 + trace of 96

O R R'' R N N t-Bu t-Bu t-Bu t-Bu

O HO O O O BF3·OEt2

HO O R' R'' R'

96 93

Scheme 21 Formation of unsymmetrical azatrioxa[8]circulene 93. Tetrahydroxy compound 95 and dihydroxy compound 96 are intermediates

Under the stated conditions for the formation of circu- R R N N lenes, we found that when reacting dihydroxycarbazoles 91 t-Bu t-Bu t-Bu t-Bu or 92 with either 2-tert-butyl-1,4-benzoquinones or 2-methoxy-1,4-benzoquinones, only one regioisomer of the fu- O O O O ran compound 96 was formed, as predicted by Erdtman’s model (see Scheme 7, section 3).20a In this case the elec- t-Bu O O tron-donating group (EDG) (R′: blue) resides ortho to the t-Bu 102 103 hydroxy group as shown in Scheme 21. This led to the re- markable regioselectivity of the quinone substituents in the Figure 9 The two regioisomers obtained from the condensation of azatrioxa[8]circulenes 97, 99, 100 and 101, which were 3,6-dihydroxycarbazole 91 or 92 with 1,4-naphthoquinone and 2-tert- butyl-1,4-benzoquinone produced in good yields with only traces of the regioisomers being present (Figure 8).34 It also became apparent that the reaction of 3,6-dihydroxycarbazole 92 with 2-tert-

butyl-1,4-benzoquinone and 2-methoxy-1,4-benzoquinone Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. always gave one regioisomer of azatrioxa[8]circulene 99, independent of the addition order. In the case of reacting 91 or 92 with 2-tert-butyl-1,4-benzoquinone and 1,4- naphthoquinone, the order of addition did influence the outcome of the reactions; when first reacting with the 2- tert-butyl-1,4-benzoquinone and later with 1,4-naphthoquinone, only one regioisomer, 102, was isolated (Figure 9).34 A reversed reaction order yielded a mixture of the two regioisomers as depicted in Figure 9. The crystal structures shown in Figure 10 highlight the almost completely planar character of 97 and 98, as pre- Figure 10 X-ray crystal structures of azatrioxa[8]circulenes 97 and 98 dicted by our geometry model (see Figure 4, section 1). The 1,4-naphthoquinone-derived product 98 features significant π–π stacking between neighboring molecules and diagonal stacks. On the other hand, azatrioxa[8]circulene their naphthalene moieties. The molecules are stacked al- 97 contains four tert-butyl groups which prevent π–π stack- ternatingly with respect to the nitrogen atoms, to accom- ing. This results in an increased distance between the π- modate the tert-butyl and propyl groups, thereby creating systems of neighboring molecules in the crystal structure.6b,34

Syn lett T. Hensel et al. Account

5 Synthesis of Diazadioxa[8]circulenes bound carbazole dimer 108 was named BICOL (analogous to BINOL). It was proposed to function as a chiral bidentate li- Similar to azatrioxa[8]circulenes, the synthetic logic be- gand in homogenous asymmetric catalysis. The short syn- hind the formation of diazadioxa[8]circulenes arises from thetic pathway to this carbazole dimer is presented in the dihydroxydibenzofuran formed in the condensation of Scheme 23. 1,4-quinone.6c In the synthesis at hand, 3,6-dihydroxycar- Tetrahydrocarbazole37 105 was oxidized with wet deac- bazole is oxidized with a fully substituted 1,4-benzoqui- tivated palladium-on-carbon in the high boiling solvent p- none to prevent any coupling reactions of the carbazole cymene, giving mainly methoxycarbazole 106 and about 1% with the 1,4-benzoquinone. This results in dimerization of of 9H-carbazole. Demethylation with concentrated hydro- the 3,6-dihydroxycarbazole 86 which, assisted by a Lewis bromic acid yielded hydroxycarbazole 107. This compound acid, leads to formation of a furan ring. Scheme 22 depicts was dimerized with copper(II) sulfate on an Al2O3 support the retrosynthesis of diazadioxa[8]circulenes 104. with dioxygen as the oxidizing agent. Enantiomeric resolution of the dimer resulted in (+)- and (–)-BICOL. A drawback R' of the described oxidative aryl coupling method and similar N R' R R methods is their unspecific nature, resulting in the forma- N tion of regioisomers. A recent study by Kozlowski and co- R R O O workers attended to the problem of regioselectivity in oxi- 38 HO OH dative coupling reactions of monohydroxycarbazoles. R R 86 They presented known coupling reactions and a novel cata- N R' 104 OH H OH H (t-BuO)2 N Scheme 22 Retrosynthesis of diazadioxa[8]circulenes 104 N PhCl 131 °C 81–87% N HO H The oxidative coupling of hydroxycarbazoles represents 109 110 a type of aryl coupling reaction that is well known and 35 O widely used in organic chemistry. The procedure usually Cl Cl requires an electron-rich aromatic system, often containing Cl Cl OH H O a hydroxy group, which is treated with an oxidizing agent. N N H N In 2002, Botman studied the oxidative coupling of hy- OH MeOH H 65 °C HO droxycarbazoles with a copper(II) sulfate (CuSO4) catalyst 38% 111 on an alumina (Al2O3) support and dioxygen as the oxi- 36 112 dant. While other catalytic systems such as [Mn(acac)3], H [CuCl(OH)]·TMEDA, or VO(acac)2 gave similar yields and se- N H R lectivity, they required a more laborious product purifica- N (PhCO2)2 tion process. The reaction catalyzed by CuSO /Al O was R CHCl3 4 2 3 r.t. HO OH chosen for its facile purification. The pure symmetrically 38% Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. OH 113 R N H H H H 114 N Pd/C (10 mol%) N HBr 48% N CuSO4/Al2O3 xylene/acetone H2O AcOH Δ Δ O2 reflux 99% 98% OMe OMe OH 107 105 106 H N H N HN

CuSO4/Al2O3 H HO OH N O2 H + xylene/acetone OH N Δ OH HO 40–50% HO N OH H 107 N 15–20% 40–50% H 108 115 116

Scheme 23 Synthesis of the hydroxycarbazole dimer, BICOL (108). Ox- Scheme 24 Oxidative coupling reactions of hydroxycarbazoles exhibit- idative coupling also gave the 4–2′ bound product in 15–20% yield36 ing low regioselectivity38

Syn lett T. Hensel et al. Account lytic system for regioselective couplings. The examples they droxycarbazoles, 91 and 92, mediated by an oxidizing agent gave on non-regioselective oxidative coupling reactions are (chloranil or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone) presented in Scheme 24. and a Lewis acid (BF3·OEt2, AlCl3 or FeCl3) in dichlorometh- In a comparison between the different reagents and ane (Scheme 26).6c conditions in the oxidative coupling of N-methyl-2-hydroxycarbazole, only tert-butylperoxide gave moderate O yields (1–3′ bond: 32%, 1–1′ bond: 29%); the use of manga- Cl Cl R nese dioxide (MnO2) resulted in lower yields (1–3′ bond: N Cl Cl t-Bu t-Bu 20%, 1–1′ bond: 18%), with other conditions giving even R O N worse yields. In an attempt to solve the low regioselectivity BF3·OEt2 CH Cl O O problem, many transition-metal salen and salan catalysts t-Bu t-Bu 2 2 71–85% were screened. A vanadium catalyst, depicted in Scheme HO OH t-Bu t-Bu 25, was found to optimize both the yields and regioselectiv- N ity. Besides the main product 119, small amounts of com- R 91 or 92 121a,b pound 118 (1–8%) and a major side product in the form of the tetramer 120 (9–30%) were observed. Scheme 26 Oxidative dimerization of N-substituted 2,7-di-tert-butyl- 3,6-dihydoxycarbazole. Blocking the 2- and 7-positions resulted in high They proposed a radical mechanism including reduction yields. a: R = propyl. b: R = benzyl of vanadium from V(V) to V(IV), followed by regeneration of the catalyst by dioxygen. To validate their assumption, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) was added to the reaction, inhibiting oxidative coupling. Exclusion of di- R R oxygen also resulted in lower yields and inhibited forma- N N t-Bu t-Bu oxidation t-Bu t-Bu tion of the tetramer. In our recent work we showed that regioselectivity was HO OH HO O not an issue, since the reactive 2- and 7-positions were 91 or 92 122 blocked by tert-butyl groups. We reported a condensation dimerization reaction of two N-substituted 2,7-di-tert-butyl-3,6-dihy-

R R t-Bu N N t-Bu N O t-Bu t-Bu t-Bu t-Bu (10–20 mol%) O R' O V oxidation N OMe HO OH Lewis acid t-Bu O O O OH HO OH R'' CHCl3, O2, r.t. –40 °C, 1–3 d t-Bu t-Bu t-Bu t-Bu 117 R'' N N R R R'' R'' 123 121 NR' Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material.

NR' R'N Scheme 27 Proposed reaction pathway for the oxidative condensation of 3,6-dihydroxycarbazole 91 or 92 to form diazadioxa[8]circulene 121 R' N OH R'' OH OH HO

118 119 1–1' bond 1–3' bond

R'' R''

NR' R'N

R' R' N N OH HO R'' R'' OH HO

120 1–1' and 1–3' bonds Scheme 25 Regioselective oxidative coupling of substituted hydroxy- Figure 11 X-ray crystal structures of diazadioxa[8]circulenes 121a and carbazoles 117 with vanadium catalysis38 121b

Syn lett T. Hensel et al. Account

We assumed that the oxidized form of the carbazole S S with a quinoid substructure 122, as shown in Scheme 27, is Ni(COD)2 1. LDA S 2,2'-bipy sulfur an intermediate in this transformation. The 3,6-dihydroxy- DMF 2. aq HCl carbazoles 91 or 92 dimerize with the oxidized compound Br Br S S 122 via a Michael-type addition, forming tetrahydroxycar- 124 125 bazole dimer 123, which can be isolated. Addition of the Lewis acid, boron trifluoride–diethyl ether complex in the presence of chloranil led to the formation of diazadi- SnH SnH S 6c S S S S oxa[8]circulene 121. vacuum HS S H The mechanism of the initial oxidation step can proceed n n pyrolysis S S via a one- or two-electron transfer. Experimental data has HSn SnH shown that the presence of chloranil is necessary for the S S S S S formation of the carbon–carbon bond. In a Michael-type SnH SnH 8 addition process, the π-system of a hydroxy-substituted 80% over 3 steps 126 carbazole attacks the β-position of the quinoid oxidized carbazole 122. After rearomatization and loss of two pro- Scheme 28 Synthesis of sulflower (8) starting from 3,4-dibromothio- phene39 tons, the dimer 123 is formed. We assume that a second oxidation and carbon–carbon bond formation occurs, followed by two condensation reactions mediated by the boron trifluoride–diethyl ether complex to form the furan flower was chosen for its resemblance to the bloom of a rings. In total, two carbon–carbon bonds and two oxygen sunflower. To prepare compound 8, a short synthesis was bridges are formed and two molecules of water are elimi- employed as presented in Scheme 28. nated, resulting in diazadioxa[8]circulene 121. The first step was a dehalogenative carbon–carbon cou- To unequivocally prove that the main products of the di- pling catalyzed by zerovalent nickel: 3,4-dibromothiophene merization of two molecules of 3,6-dihydroxycarbazoles 91 (124) was reacted with bis(cyclooctadiene)nickel [Ni(cod)2] or 92 are the structures shown, single crystals of 121a having 2,2′-bipyridine as the ligand to form the cyclic te- (R = propyl) and 121b (R = benzyl) were grown by slow tramer 125. Under strongly basic conditions, achieved with evaporation of dichloromethane from a mixture of di- excess lithium diisopropylamide (LDA), cyclotetrathio- chloromethane–ethanol (1:1) (Figure 11). The resulting phene 125 was treated with elemental sulfur. After acidic pale yellow needles were suitable for single-crystal X-ray work-up, the tetrathiophene product 126 with all hydro- crystallography. gens replaced by polythiolates was formed. The octapoly- Both diazadioxa[8]circulene derivatives 121a,b are al- thiol-tetrathiophene 126 was converted into octathia[8]cir- most completely planar with small deviations in the bond culene 8 by vacuum pyrolysis. In a more recent paper, Ne- lengths at the COT center of the molecule, being compara- najdenko described the synthesis of ble to those in tetraoxa[8]circulenes (1.40–1.44 Å). Even tetrathiatetraselena[8]circulene by simply replacing the though a large flat cyclic conjugated system is apparent, sulfur powder in their previous synthesis with selenium 6f there is no π–π stacking visible due to the presence of the powder. Elemental analysis, high-resolution mass spec- Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. four tert-butyl substituents.6c trometry and NMR spectroscopy confirmed the identity and structure of octathia[8]circulene 8. Final structural proof was obtained in the form of matching calculated and 6 Synthesis of Other Heterocyclic [8]Circu- experimental single-crystal X-ray data. Sulflower is a highly lenes symmetrical and planar molecule with dense crystal packing. Nenajdenko emphasized the importance of the elec- Besides tetraoxa-, azadioxa- and diazadioxa[8]circu- tronic properties of organosulfur compounds,39 since they lenes, a number of systems that qualify as hetero[8]circu- are possible candidates for organic light-emitting devices,40 lenes have been described in the literature. Only com- thin-film transistors41 and other applications.42 pounds with a planar COT core, fully cyclo-annulated by ar- In the same year, Osuka and co-workers described a te- omatic rings of which at least one is a heterocycle, qualify trameric porphyrin sheet with an embedded tetraaza[8]cir- as hetero[8]circulenes. culene subunit.6g This porphyrin sheet was prepared, start- One of the first sulfur-containing hetero[8]circulenes ing with a Rothemund synthesis, where pyrrole conden- was described in 2006 by Nenajdenko and co-workers.39 sates with two molecules of an aldehyde and a pyrrole Their octathia[8]circulene 8 consists of eight thiophene trimer under acidic conditions. Addition of 2,3-dichloro- moieties, ortho-fused to form the COT core. The name sul- 5,6-dicyano-1,4-benzoquinone (DDQ) resulted in oxidation and reconjugation of the π-system. Multiple reaction steps consisting of coupling reactions with silver hexafluoro-

Syn lett T. Hensel et al. Account

Ar Ar 1. CF3CO2H t-Bu CH2Cl2 N N O 2. . Cl Cl Zn Ar N N O O t-Bu Ar CN CN

3. Zn(OAc)2 AgPF6 HN N N N N MeOH/CHCl3 MeCN Zn Ar Zn Ar NH HN N N NN

127 128 Ar racemic mixture HN Ar Ar

O Cl CN N N N N Ar Zn Zn Ar Cl CN N N N N AgPF6 O MeCN 129 Sc(OTf)3, toluene

40% all 6 30% possible stereoisomers N N N N of the tetramer Ar Zn Zn Ar are formed NN NN

Ar Ar 130 Scheme 29 Synthesis of porphyrin tetramer 130. The tetraaza[8]circulene subunit with a COT core is highlighted in red43

MeO OMe phosphate (AgPF6) in acetonitrile and enantiomeric resolu- MeO OMe Br Br NBS tions, followed by oxidation with a mixture of DDQ and MeO OMe MeO OMe H2SO4 scandium(III) triflate [Sc(OTf)3] in toluene, gave the por- TFA Br Br phyrin sheet 130 in low yield. A more efficient synthesis 0 °C to r.t. Br Br (Scheme 29), was introduced by Osuka and co-workers two 58% MeO OMe years later.43 In their more recent work, they refrained from MeO OMe Br Br using enantiomeric resolution after the dimerization and MeO OMe MeO OMe 131 132 tetramerization steps (with AgPF6 in MeCN).

The aromaticity of the porphyrin subunits and the an- 1. n-BuLi 1. n-BuLi Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. tiaromaticity of its central COT were studied extensively by S powder Se powder THF THF NMR spectroscopy, theoretical methods [nucleus-indepen- –78 °C to r.t. –78 °C to r.t. 2. Cu powder 2. Cu powder dent chemical shift calculations (NICS)], optical spectrosco- 250 °C 250 °C py and electrochemical methods. Geometry optimizations, 15% 19% performed by Osuka, depict a completely planar porphyrin MeO OMe MeO OMe S Se 6g sheet and central COT. The COT core was shown to have a MeO OMe MeO OMe strongly antiaromatic character, while the zinc–porphyrin subunits retained a weakened aromatic character. Ligand S S Se Se binding studies aimed at examining aromaticity and antiar- MeO OMe MeO OMe omaticity are presented in section 8 of this account. S Se Recently, Wong and co-workers introduced a short syn- MeO OMe MeO OMe thetic route to form tetrathia- 133 and tetraseleno[8]circu- 133 134 lene 134 starting from octamethoxytetraphenylene 131.44 Scheme 30 Synthesis of tetrathia[8]circulene 133 and tetraseleno[8]circulene 134 derived from cyclic octamethoxytetraphenylene Starting material 131 was prepared via two-step syntheses 13144 starting from either 2,2′-dibromo-4,4′,5,5′-tetramethoxybiphenyl or 2,2′-diiodo-4,4′,5,5′-tetramethoxybiphenyl.45 The Tetraphenylene 131 was reacted with N-bromosuccin- synthesis of the cyclic sulfur- and selenium-bridged tetra- imide (NBS) in trifluoroacetic acid (TFA) and sulfuric acid phenylenes is presented in Scheme 30. (H2SO4) to achieve an eight-fold bromination. The resulting

Syn lett T. Hensel et al. Account

octabromide 132 was lithiated with an excess of n-butyl- low yield low yield multistep multistep lithium (n-BuLi), replacing all the bromine atoms. The sub- synthesis synthesis sequent addition of selenium or sulfur powder led to the polyselenolate or polythiolate intermediate, respectively. Fi- nally, thermal treatment (250 °C, under argon) of the intermediates with copper powder yielded the hetero[8]circulenes 133 and 134. Single crystal X-ray data revealed tetraphenylene 131 and tetraselena[8]circulene 134 were saddle- shaped, while tetrathia[8]circulene 133 was completely pla- 135 139 nar. This disparity arose due to the difference in bond KMnO4 KMnO4 lengths of the C–Se bonds (1.86 Å) and the C–S bonds (1.72

Å) in the respective tetrahetero[8]circulenes. The crystal HO2C CO2H CO2H structures also showed no π–π stacking interactions, as these were prevented by the methoxy groups. Weak C–H···π interactions were however observed (~2.8–3 Å). Analysis of CO2H HO C CO H HO C the optical properties by UV/Vis and fluorescence spectro- 2 2 2 CO2H 136 140 scopy revealed a λmax red shift of the circulenes compared to CH N tetraphenylene 131. A λmax red shift of the seleno com- 2 2 CH2N2 pound 134 compared to the sulfur compound 133 was also MeO2C CO2Me CO2Me observed, with both circulenes displaying similarly shaped spectra. In accordance with UV/Vis spectroscopy, their cyclic voltammograms displayed relatively small highest oc- CO2Me cupied molecular orbital–lowest unoccupied molecular or- MeO2C CO2Me MeO2C bital (HOMO–LUMO) gaps. The investigations on the aro- CO2Me 137 141 maticity and antiaromaticity, including the calculated NICS H4P2O7 H4P2O7 240 °C 240 °C values, are presented in section 8 of this account. O O O Very recently, Osuka and co-workers reported on the synthesis of a tetraaza[8]circulene, the first of its kind.46 The synthetic protocol employed an oxidative fold-in fusion reaction, where a 1,2-phenylene-bridged cyclic tetrapyrrole was converted into tetranaphthotetraaza[8]circulene in O O O O 96% yield. X-ray diffraction data confirmed the planarity of 138 142 NH2NH2·H2O NH2NH2·H2O the product, which is important in the study of antiaroma- (NaOC2H4)2O (NaOC2H4)2O ticity.

7 Synthesis of Structurally Related Com- Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. pounds

14 143 The compounds described in this section feature, in contrast to the hetero[8]circulenes, a partly annulated COT Scheme 31 Synthesis of tetramethano[8]circulene 14 and trimetha- 6l core. They are either derivatives of the cyclic versions of tet- no-o-tetraphenylene 143 raphenylene, tetrathiophene or dithienophene. An early example was described by Hellwinkel and Reiff The starting materials, tetramethyltetraphenylenes 135 in 1970.6l They produced a compound with a presumably and 139, accessible by a low-yielding multistep synthesis, planar COT core, annulated by four benzene rings which were first oxidized with potassium permanganate (KMnO4) were themselves connected by methylene bridges. The syn- to yield the tetracarboxylic compounds 136 and 140.47 thetic pathways resulting in tetramethano-o-tetraphenyl- Treatment with diazomethane produced the corresponding ene 14 and trimethano-o-tetraphenylene 143 are depicted methyl esters 137 and 141, which were reacted with poly- in Scheme 31. phosphoric acid. The obtained cyclic fluorenones 138 and 142 yielded tetramethano-o-tetraphenylene 14 and tri-

Syn lett T. Hensel et al. Account methano-o-tetraphenylene 143 when reduced with hydra- Silyl-containing cyclic tetrathiophene 147 was synthe- zine in sodium diethylene glycolate. The products were as- sized, starting with a dilithiation of dibromo-dithiophene sumed to be planar based on steric considerations. 144 and subsequent treatment with dichlorodimethylsilane In 2010, attempting to create cyclo-annulated planar to give 145. Dimerization to form 147 was achieved by COT systems, Iyoda and co-workers45 published the syn- dilithiation, reaction with tridecafluorohexyl iodide and re- thetic routes for three different cyclic tetrathiopenes with acting the obtained diiodide 146 with n-BuLi and copper(II) either two dimethylsilyl, two sulfur or two sulfoxide bridg- chloride (CuCl2). Directly reacting 145 with n-BuLi and Cu- es on opposite sides of the compounds, respectively. The re- Cl2 yielded product 147 as well. The sulfur-bridged cyclic action pathways are shown in Scheme 32. tetrathiophene 151 and the sulfoxide-bridged cyclic tetrathiophene 155 both originated from dithienothiophene (a) S 1. n-BuLi, THF S 147, which was described in an earlier paper by Yoshida, Iy- Br –100 °C oda and co-workers.48 Bis(4-bromothiophen-3-yl)sulfane 2. Me2SiCl2, THF Si Br 89% was converted into dithienothiophene 148 via a palladium- S catalyzed cyclization. To produce the sulfur-bridged COT S compound 151, dithienothiophene 148 was selectively 144 145 1. n-BuLi dilithiated and reacted with trimethylsilyl chloride (TMSCl) 1. n-BuLi, THF, 0 °C THF 2. C F I, THF to give compound 149, which was itself dilithiated again 6 13 0 °C 52% 2. CuCl2 and treated with CuCl2 to yield the trimethylsilyl-protected 33% cyclic dimer 150. Deprotection with tetrabutylammonium S S S fluoride (TBAF) resulted in the cyclic tetrathiophene 151 I 1. n-BuLi, THF, 0 °C 2. CuCl2 with two opposing sulfur bridges. The same reaction path- Si Si Si 51% way was applied to give the oxidized cyclic tetrathiophene I 155. Oxidation with m-chloroperoxybenzoic acid (MCPBA) S S S was required, preceding the TMS protection step. The single 146 147 crystal X-ray and calculated optimized structures con- TMS 1. n-BuLi, THF S 1. n-BuLi, THF S curred concerning the planarity of the molecules. The sul- (b) –78 °C 0 °C 2. TMSCl 2. CuCl2 fur-bridged compound 151 was the most planar (bent an- S S 75% 45% gle: 4.3°), followed by the sulfoxide-bridged compound 155 (7.0°) and the dimethylsilane-bridged compound 147 (19°). S TMS S 148 149 Following these findings, the magnetic ring currents and HOMO–LUMO energy gaps have been studied by NMR

TMS TMS spectroscopy, UV/Vis spectroscopy and cyclic voltammetry S S S S (CV). In the proton NMR spectrum, the α-protons of all the TBAF THF heteroatom-bridged cyclic tetrathiophenes (147: δ 7.26, S S S S 100% 151: δ 6.97 and 160: δ 7.99) experienced an upfield shift compared to the corresponding dimeric analogs (145: δ S S S S

TMS TMS 7.53, 148: δ 7.39 and 152: δ 8.29). However, the α-protons Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. 150 151 of saddle-shaped cyclic tetrathiophene without bridging (c) TMS S m-CPBA S 1. n-BuLi, THF S heteroatoms (δ 7.37) experienced a downfield shift com- –78 °C CH2Cl2 r.t. O 2. TMSCl O pared to 3,3′-bithiophene (δ 7.20). A distinct trend became S S S 94% O 89% O apparent: the compounds with the highest planarity experience the highest upfield shifts. The shifts presumably S S TMS S originate from a paratropic ring current induced by the COT 148 152 153 core. Decreased diatropicity of the thiophene rings as the

1. n-BuLi TMS TMS cause was ruled out by comparison of the NICS values and THF S S S S the differences in chemical shift values of the synthesized 0 °C TBAF THF 2. CuCl2 O O O O compounds and a few related compounds. Comparing the S S S S 32% O O 100% O O colors of solutions of the tetrathiophenes gave an indication of the differences in the HOMO–LUMO gap size: the silyl S S S S TMS TMS compound 147 was orange (λmax = 483 nm) in solution, the 154 155 oxidized sulfur compound 155 was red (λmax = 575 nm), and

Scheme 32 Synthesis of bridged tetrathiophenes. (a) Silyl-bridged the sulfur compound 151 was purple (λmax = 618 nm). The 147. (b) Sulfur-bridged 151. (c) Sulfoxide-bridged 15545 increasing planarity of the molecules was accompanied by a decreasing HOMO–LUMO gap size, which was in accordance with the CV results.

Syn lett T. Hensel et al. Account

Iyoda’s idea of thiophene-annulated cyclooctatetraenes copper bronze Zn/HCl was further pursued by Nishinaga et al., who in 2013 pub- PhNO2 lished their work on the synthesis of dithienophene com- Δ MeO NO2 AcOH MeO NO2 MeO NO2 pounds with a planarized COT core and with directly at- I tached protons.49 The synthetic pathway toward dithieno- 162 thiophene-COT 161 comprised six steps (Scheme 33). 163 1. n-BuLi TMS TMS TMS 1. NaNO Et O S 1. n-BuLi S S 2 2 aq. HCl 2. TMEDA Et2O –78 °C C2H5PPh3I MeO NH2 2. KI MeO I 3. CuCl2 S 2. DMF S n-BuLi S MeO NH2 62% MeO I 29% 29% 89% CHO TMS S TMS S TMS S 149 156 157 164 165

1. n-BuLi S 1. MgBr . S OTMS BBr3 Et2O CHO 2. TMSCl –78 °C DMAP MeO OMe CH2Cl2 HO OH 2. DMF S Et3N S MeO OMe 100% HO OH 37% 64% S S TMS TMS 158 159 166 167 S OTMS 1. K2CO3 S nd Grubbs' 2 gen. cat. 2. Martin sulfurane Tf2O CH2Cl2 S t-BuOK Py S CH2Cl2 TfO OTf 87% 41% TfO OTf S 100% TMS S 160 161 168 Scheme 33 Synthesis of dithienophene-annulated cyclooctatetraene 16149 Scheme 34 Synthesis of tetratriflate 168, a precursor of dioxatetraphenylene 1696h,51

In the first reaction, dithieno[3,4-b:3′,4′-d]thiophene 149 was formylated by lithiation with n-BuLi in diethyl quired cyclic tetraphenylene 168 as the starting material, ether (Et2O) followed by addition of N,N-dimethylforma- which was obtained by a procedure described in their pre- mide (DMF). The resulting aldehyde 156 underwent a Wit- vious work from 2005 (Scheme 34).6h tig reaction to form propylene 157. After a second formyla- Tetratrif late 168 was reported to be the main product in tion, and a subsequent Grignard reaction with vinylmagne- a synthetic pathway starting with an Ullmann coupling of sium bromide, diene 159 was formed. The alkene moieties two molecules of 2-iodo-3-nitroanisole (162) with copper

in 159 were utilized in a metathesis reaction with the sec- bronze in nitrobenzene at 190–200 °C. 2,2′-Diamino-6,6′- Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. ond generation Grubbs catalyst to yield the cyclooctatriene dimethoxybiphenyl (164) was then obtained by reducing 160. Finally, elimination of TMS under oxidative conditions the nitro groups of biphenyl 163 with zinc and hydrochloric (Martin sulfurane) with potassium tert-butoxide (t-BuOK) acid.51 The conversion of the amines into iodides was ac- yielded the dithienothiophene-COT 161. X-ray and NMR complished by treatment with sodium nitrite in hydrochlo- data, as well as the calculated structure and NICS values in- ric acid followed by addition of potassium iodide (KI) to dicated a planar compound 161 with a magnetically antiar- give 165. After dilithiation of 165 and addition of N,N,N′,N′- omatic COT-core. The protons attached directly to the COT tetramethylethylenediamine (TMEDA), the dilithium inter- core experienced a paratropic ring current and the magnet- mediate was oxidatively coupled in the presence of CuCl2 to ic antiaromaticity was higher than in the previous tetra- form cyclic tetramethoxytetraphenylene 166. Deprotection thiophenes presented by Iyoda in 2010.45 Optical spectros- of the methyl groups with boron tribromide followed by copy and cyclic voltammetry revealed a considerably small- treatment with triflic anhydride (Tf2O) and pyridine yielded er HOMO–LUMO gap. The analytical data concerning the tetratriflate 168. magnetic antiaromaticity of the COT is further discussed in As shown in Scheme 35, tetratriflate 168 was found to section 8 of this account. undergo an intramolecular reaction forming two furan In 2014, Wong and co-workers described the synthetic rings upon treatment with tetrakis(triphenylphos- pathways for the preparation of diheteroatom-bridged tet- phine)palladium(0) [Pd(PPh3)4] and potassium phosphate raphenylenes with oxygen, nitrogen, sulfur and selenium (K3PO4) in DMF at 140 °C for 24 hours. Wong et al. assumed bridges.50 Their synthesis of dioxatetraphenylene 169 re- that trace amounts of water partially hydrolyzed the triflate

Syn lett T. Hensel et al. Account

in the starting material. The resulting hydroxy group tone)dipalladium(0) [Pd2(dba)3], sodium tert-butoxide caused intramolecular coupling to form the furan moieties (t-BuONa) and tri-tert-butylphosphine [(t-Bu)3P] in toluene in 169. The synthesis of the nitrogen-, sulfur-, and seleni- gave the N-phenyl-bridged tetraphenylene 171. The sulfur- um-bridged compounds 171, 173, 174 and 176 (Scheme 35) and selenium-bridged compounds were also derived from required a different starting material, 1,8,9,16-tetrabromo- the tetrabromo compound 170. Treatment of 170 with n- tetraphenylene (170). It was prepared in two steps from BuLi and iodine (I2) in tetrahydrofuran, followed by

2,2′,6,6′-tetrabromobiphenyl, as described by Iyoda and CuI/DMEDA and potassium sulfide (K2S) in acetonitrile Kabir.52 At first, tetrabromobiphenyl was lithiated, followed (140 °C) resulted in the formation of two thiophene moi- by reaction with zinc(II) bromide to form dibenzozincacy- eties in product 174. When tetrabromide 170 was lithiated clopentadiene. In a second reaction, 1,8,9,16-tetrabromo- with n-BuLi and reacted with selenium powder in tetra- tetraphenylene (170) was obtained via dimerization involv- hydrofuran (–78 °C), the obtained bis(diselenium)-bridged 50 ing catalysis with CuCl2. Wong utilized 170 in a reaction 175 product was subjected to thermal deselenation with with sodium azide, copper(I) iodide (CuI) and N,N′-dimeth- copper powder (250 °C) to yield diseleno-bridged tetra- ylethylenediamine (DMEDA) at 120 °C in dimethyl sulfoxide phenylene 176. Single-crystal X-ray structures and calculat- (DMSO) to form di-9H-carbazole 172, followed by reaction ed structures indicated that all the diheteroatom-bridged with benzyl bromide and sodium hydride in tetrahydrofu- tetraphenylenes were saddle-shaped, however, the bent an- ran to yield N-benzylated compound 173. They also found gles were significantly smaller than those in tetraphenylene that treatment of 170 with aniline, tris(dibenzylideneace- and decreased in the order Se > S > N > O. An exception was N-phenyltetraphenylene 171, which had a significantly (a) Pd(PPh3)4 K3PO4 smaller bent angle (8.89°) than the other compounds DMF TfO OTf 140 °C (25.56° to 37.43°). It appeared that the cyclic tetraphenyl- O O TfO OTf 68% ene required more than two heteroatom bridges to achieve a fully planar structure. UV/Vis spectra revealed a red shift

of the λmax for the heteroatom-bridged compounds com- 168PhNH2 169 Pd2(dba)3 pared to cyclic tetraphenylene. The shift of λmax appeared to t-BuONa (b) be in an inverse relationship with the bent angles, in accor- (t-Bu)3P toluene dance with the results obtained by Iyoda.45,50 Br Br 120 °C PhN NPh Br Br 85% Tetramesitylene compound 182, an all-carbon [8]circulene, was recently described by Tobe and Nakano.53 The potential tetra-radicaloid system of 182 was investigated for 170 171 its structure and electronic properties by the means of DFT

CuI, NaN3, DMEDA calculations and experimental data. The synthetic pathway Me2SO, 120 °C 45% toward [8]circulene 182 is presented in Scheme 36.

NaH BnBr R R THF 0 °C to r.t. HN NH BnN NBn AlCl3 85% SOCl2 70 °C CH2Cl2 Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. R R R R 79% (2 steps) 172 173 R R R: CO2H R: COCl (c) 1. n-BuLi, I2 136 177 THF, –78 °C to r.t. 2. CuI, K2S, DMEDA R: TfOH Br Br MeCN, 140 °C LiAlH4 4·CHOHMes S S Et2O CH2Cl2 Br Br 69% R: COMes 179 + 178 40% (2 steps) 3·CHOHMes / 1·COMes Mes 180 Mes 170 174 n-BuLi, Se DDQ THF, –78 °C toluene 67% 50 °C Mes Mes Mes Mes 98% copper powder Se Se 250 °C Se Se Se Se 100% Mes Mes 181 182 175 176 Scheme 36 Synthesis of tetracyclopenta[def,jkl,pqr,vwx]tetraphenyl- Scheme 35 Synthesis of oxygen-, nitrogen-, sulfur-, and selenium- ene derivative 18253 bridged tetraphenylenes50

Syn lett T. Hensel et al. Account

The starting material, tetracarboxylic acid 136, was ob- site is true for antiaromatic compounds: the localization of tained via the literature procedure described by Hellwinkel double bonds, and therefore absence of resonance stabiliza- and Reiff.47b After formation of the acid chloride 177 with tion leads to a smaller HOMO–LUMO gap. A consequence of thionyl chloride (SOCl2), a Friedel–Crafts reaction with mes- the change in HOMO–LUMO gap size, and therefore elec- itylene and aluminum chloride yielded tetraketone 178. tronic properties, is a change in optical properties, influ- Treatment with lithium aluminum hydride (LAH) resulted encing the absorption and emission spectra. The altered in a mixture consisting of the incomplete reduction product electronic properties are of interest in the field of organic 180 and tetrahydroxy compound 179. Addition of triflic semiconductors, which require compounds with a small acid gave the dihydro product 181, which was subjected to gap size.56 oxidation with DDQ to yield 1,4,7,10-tetramesityltetracy- Classifying aromatic and antiaromatic systems by their clopenta[def,jkl,pqr,vwx]tetraphenylene 182. Analysis of magnetic behavior is possibly the most valuable property in compound 182 by 1H NMR spectroscopy revealed the pro- discerning the concepts.56 An overall diatropic ring current ton signal of the tetracyclopentantetraphenylene ring to be is characteristic for aromatic systems, and an overall para- significantly shifted upfield, at 2.85 ppm, indicating a tropic ring current is representative for antiaromatic sys- strong paramagnetic shielding effect due to the central COT tems. Because of these inherent magnetic properties, NMR system and a considerably lowered aromaticity of the cyc- spectroscopy is a powerful tool to evaluate the aromatic or lo-annulated ring system. Tobe and Nakano’s NICS(1) calcu- antiaromatic character of a molecule. The chemical shifts lations supported these observations with a large positive observed in proton NMR spectra can be associated with value for the COT core (10.15), positive values for the qui- aromaticity in the case of a downfield shift caused by a dia- none-like substructure (4.60) and cyclopentane ring (7.86), tropic ring current on the outside of the ring, or an upfield and a small negative value for the benzene-structured ring shift for nuclei positioned on the inside or above the ring. (–1.22). The single-crystal X-ray structure of compound Due to the paratropic ring current of antiaromatic systems, 182 revealed a completely planar COT and an approximate these predictions are inversed. The magnetic properties of

D2h structure. The COT core itself experiences significant the ring current can also be predicted reasonably well by bond length fluctuations.53 calculation of NICS values.56 In this computational method, a ghost atom is placed in the center of a ring system (NICS(0)) or typically one Ångstrom above it (NICS(1)) to 8 Hetero[8]circulenes and Related Com- calculate the locally increased or decreased magnetic effect pounds as Tools to Study Aromaticity and An- the ring system has on the ghost atom. Large negative val- tiaromaticity ues hint at local aromaticity, whereas large positive values indicate local antiaromaticity. Values around zero are likely The term aromaticity is most commonly used to de- to predict local non-aromatic properties. Similar sized ring scribe a cyclic delocalized electron system. Defining aroma- systems can be compared directly, while systems of differ- ticity has been a daunting task, despite the numerous ex- ent sizes must take the ring size effect into account. It is amples of compounds and the general perception that aro- also important to only compare NICS values that have been maticity equals stability. As such, its reciprocal concept, calculated at the same theoretical level. The curious proper-

antiaromaticity, has proven even more difficult to study, as ties and variations of aromatic and antiaromatic systems Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. compounds designed with cyclic 4n π-systems often prefer underline the importance of any investigation.57 bent structures and localized double bonds, as opposed to One of the first tetra-annulated bicyclo COT systems the planar, delocalized structures ideally needed for study. was described by Richter et al. in 1991.58 They explored the Arriving at a definition can be attempted by analyzing the possibility of forming a planar dianionic COT despite steric four properties usually associated with aromaticity: reac- hindrance. The synthesis of tetrakis(bicyclo[2.2.2]octane)- tivity, structural features, energetic properties and magnet- cyclooctatetraene 184 is presented in Scheme 37, omitting ic behavior, and compare these to how antiaromatic sys- the preparation of the dibromo tetramer 183.59 tems are expected to act. This section will mainly address the structural, energetic, and magnetic aspects. Br Na+ Both aromatic and antiaromatic systems feature planar structures. The delocalization of electrons in aromatic com- THF 0 °C pounds stabilizes the system energetically and chemically. For antiaromatic compounds, the delocalized double bonds, however, do not represent a minimum in energy, and as Br such, systems designed to be antiaromatic exhibit localized 184 185 183 20% 40% double bonds. Aromatic molecules feature a relatively large gap between the HOMO and LUMO,54 which increases fur- Scheme 37 Synthesis of tetrakis(bicyclo[2.2.2]octane)cyclooctatetraene 184 and tris(bicyclo[2.2.2]octane)benzene 18558 ther with successive addition of aromatic rings.55 The oppo-

Syn lett T. Hensel et al. Account

Dibromobicyclo[2.2.2]tetramer 183 was reacted with was then lithiated and reacted with tributyltin chloride sodium naphthalenide in tetrahydrofuran at 0 °C yielding (n-Bu3SnCl) to yield bicyclo tributyltin derivative 189. tetrabicyclo[2.2.2]-COT 184 (20%) and a larger amount of Treatment with iodine followed by oxidation with potassi- tribicyclo[2.2.2]benzene 185 (40%). Analysis of the single- um tert-butoxide gave diiodide 191. At this point in the crystal X-ray structure revealed bicyclo[2.2.2]octane 184 to synthetic pathway, the final reaction step could be opti- be saddle-shaped, while benzene compound 185 featured a mized to either yield only tribicyclo benzene 192 (by lithia- 13 planar center. The C NMR spectrum of bicyclo-annulated tion, addition of CuI and CuCl2) or to afford a mixture of

COT 184 showed four signals reflecting its D2d symmetry. tetrakisbicyclo COT 193, trisbicyclo benzene 192 and a bi- Optical spectroscopy revealed the typical UV/Vis absorp- cyclo[2.1.1] dimer 194 (by lithiation and addition of only tions of a COT chromophore. An interesting feature is repre- CuI). When comparing the analytical data of the planar bi- sented by the possibility to produce the dianion by reduc- cyclo[2.1.1]-COT 193 and the saddle-shaped bicyclo[2.2.2]- tion with potassium mirror in tetrahydrofuran. The proton COT 184, large differences became apparent. The UV/Vis and carbon NMR spectra of the dianion of 184 imply pla- spectra revealed a significant red shift of λmax (Δλ 177 narity: the COT carbons are shifted upfield, the bridging nm = 7 eV) from saddle-shaped compound 184 (282 nm) to ethylene carbons give one signal instead of two and the dia- planar compound 193 (459 nm). The potential of both oxi- tropic ring current causes a downfield shift of the bridge- dation waves in the cyclic voltammetric studies increased head protons. by approximately 0.4 V from bicyclo[2.2.2]octane 184 to bi- A decade later, another study concerning tetrabicycloal- cyclo[2.1.1]hexane 193. Komatsu also compared the 1H kane-annulated cyclooctatetraene and the corresponding NMR spectra of the COT-core compound 193 with that of benzene emerged. Tetrakis(bicyclo[2.1.1]hexane)cycloocta- benzene-core compound 192. The bridgehead hydrogen at- tetraene 193 and tris(bicyclo[2.1.1]hexeno)benzene 192 oms were deemed to be influenced the most by the ring were synthesized in 2001 by Komatsu and co-workers current from the COT core, since they are positioned in the (Scheme 38).60 It was one of the first planar COT systems same plane as the COT core. The observed difference in without an annulated aromatic system forcing it to planari- chemical shift however, was only 0.18 ppm. Calculated NICS ty. values and magnetic susceptibility exaltations (Λ) indicated an aromatic benzene core in 192 (NICS value of –8.0 com- t-BuLi TPSH pared to –9.7 for D6h benzene) and an antiaromatic COT in O N Tris THF Li Et2O N –78 °C to 0 °C H 193 (NICS value of 10.2 compared to 27.2 for standard pla- 77% nar D4h COT), therefore a greater downfield shift, due to the 186 187 188 paratropic ring current of the antiaromatic COT core, was expected.60 KOt-Bu n-Bu3SnCl SnBu I2 I To study the antiaromaticity of an annulated planar COT 3 THF –78 °C CCl4 I system, Osuka and co-workers developed a synthetic path- 88% (2 steps) 78% 94% 6g I way to form the porphyrin tetramer 130. This porphyrin 189 190 sheet incorporated a tetraaza[8]circulene moiety. In a series of papers ranging from 2006 to 2008, the magnetic 1. n-BuLi, THF, –78 °C ring-current effect of the COT core and the porphyrin sub- Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. 2. CuI, –78 °C to –45 °C I 3. CuCl2, –78 °C to r.t. units was analyzed by coordinating imidazoles and pyri- 40,61 43% dines to the zinc atoms bound within the porphyrins. I The synthesis of a tetra-annulated porphyrin containing 191 192 COT 130 is shown in Scheme 29 (see section 6). Both ligands (1,4-bis[(1-methyl-1H-imidazol-2-yl)ethynyl]ben- 1. n-BuLi THF zene 195 and bis-methylimidazole porphyrin 196) were –78 °C 2. CuI shown to form 2:1 complexes with the porphyrin sheet. I –78 °C to r.t. The imidazoles coordinated to two zinc atoms in the por- I phyrin sheet, causing them to be diagonally locked onto the COT core (Scheme 39). The resulting complexes were stud- 1 193 192 194 ied by H NMR spectroscopy (the observed protons are 21% 34% 5% marked in red in Scheme 39) and the results were com- Scheme 38 Synthesis of tetrakis(bicyclo[2.1.1]hexane)cyclooctatet- pared to DFT calculations. When comparing the chemical raene 193 and tris(bicyclo[2.1.1]hexeno)benzene 19260 shifts of the protons residing directly above the COT core from the bound and unbound ligands, large downfield The synthetic route to cyclo-annulated COT 193 began shifts of 3.78 ppm for the linear ligand and 5.29 ppm for the with the reaction of ketone 186 with 2,4,6-triisopropylben- porphyrin ligand became apparent. Osuka interpreted this zenesulfonyl hydrazide (TPSH). The resulting product 187 observation as an effect of a strong paratropic ring current

Syn lett T. Hensel et al. Account

C6H13

CH3 N NH N N H

N N HN N H N N H H3C N Zn N N H H N N N Zn N N N Ar Ar H13C6 H Zn Zn H Zn N 195 196 N N N N Zn Zn Ar Zn Zn Ar Zn +0.58 +0.22 N N N N Hβ Hα 130–1952 +0.26 130–1962 N N a +0.51 N N N N H Zn Hb Zn 197 Ar Zn Zn Ar +0.34 Zn N NN NN Hd +0.11 Zn +0.42 +0.47 +0.07 N He γ β α Hc N H H H N Ar Ar +3.17 g f N N 130 N H N H +0.69 -0.46 N 200 Zn N 198 N N Zn Zn N Zn +0.31 +0.27 +0.38 +0.00 N Zn Zn Zn Hγ Hδ Hβ Hα Zn N N 1302 –1974

(1302 –1984, 1302 –1994) 199 130–2002

Scheme 39 Complexation of Osuka’s porphyrin sheet 130 with different ligands. Examined protons are highlighted in red. The differences in the proton chemical shifts between bound and unbound ligands for compounds 197–200 are presented next to the corresponding protons in ppm.6g,61 The ligands below the porphyrin sheets are omitted for clarity

experienced by the aromatic protons in the complexed phyrin sheet 130 in the form of 1,3-bis(pyridin-3- form, which led to strong magnetic deshielding. Protons lo- ylethynyl)benzene (200), 4,4′-bipyridine (197), 1,4-di(pyri- cated on top of the porphyrin moieties exhibited upfield din-4-yl)benzene (198) and 4,4′-di(pyridin-4-yl)-1,1′-bi- shifts (–0.01 to –0.83 ppm), which were attributed to a phenyl (199) were employed62 (Scheme 39). All three linear weakened diatropic ring current above the zinc porphyrins. pyridine ligands appeared to form 2:4 complexes with the DFT calculations were conducted to gain understanding of porphyrin sheet, while the bent ligand 200 was found to the unusual chemical shift changes observed in the proton complex the porphyrin sheet in a 1:2 stoichiometry. The NMR spectra of the bound ligands. The NICS values, calcu- proton NMR data of the bound linear ligands, showing a lated for the COT core of the zinc(II) porphyrin tetramer simple signal pattern, led Osuka and co-workers to the con- (61.7) and the tetramer without zinc(II) (21.7), were large clusion that these ligands underwent free rotation within and positive, hinting at a strong paratropic ring current. The the complex. On comparing the chemical shifts from the COT core was therefore assumed to have a magnetically proton NMR spectra of the unbound and bound ligands,

strong antiaromatic character. Small positive and negative two trends became apparent: first, the deshielding influ- Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. NICS values were calculated at the centers of different rings ences of the porphyrin sheet decreases with increasing li- in the porphyrin subunits, suggesting substantially weak- gand length, and second, the order of magnitude in chemi- ened aromaticity, down to a level where some of the rings cal shift was found to be: Hβ > Hγ > Hδ > Hα. Due to free rota- could not be considered as being aromatic anymore. These tion, the examined protons experience only an average of small values (–1.1 to 2.8) stand in contrast to the large neg- the ring-current strength above the porphyrin subunit. The ative NICS values (–16.5 to –21.7) calculated for the individ- non-linear ligand, 1,3-bis(pyridin-3-ylethynyl)benzene ual porphyrin and magnesium porphyrin, which would in- (200), was studied because its protons are positioned at dif- dicate a strong aromatic character of the electronic system ferent heights above the porphyrin subunit and the COT of the isolated subunits.6g It is assumed that the strong core. When comparing the chemical shifts of the protons paratropic ring current of the COT core influences the 18π above the porphyrin subunit, only Hf is far enough away aromatic porphyrin systems, weakening them to the ob- from the COT core to experience a net diatropic ring cur- served extend. rent. By contrast, Hg resides closer to the COT core and is in- Subsequently, Osuka and co-workers presented addi- fluenced distinctly stronger by the paratropic ring current. tional investigations on the porphyrin sheet 130 with dif- The induced magnetic effect changes from an upfield to ferent ligands.61 Their goal was to study the distance depen- downfield shift with increasing distance to the porphyrin dency of magnetic effects with respect to protons on a li- plane, as seen in the difference in the downfield shift ob- gand. Ligands with pyridine moieties for zinc(II) served for the signals of Hf to He. Proton Hc resided directly coordination and protons with varying distances to the por- on top of the COT core and experienced the strongest para-

Syn lett T. Hensel et al. Account tropic ring current. The magnetic effect of the COT core was –7.61 O –7.70 O also found to decrease with increasing distance of the nu- O –9.42 –9.47 –7.59 –7.31 –7.84 –7.56 –8.22 c b a –9.20 –10.05 –6.77 –10.03 –7.03 –6.86 clei, based on the chemical shifts of protons H , H and H . –7.89 –9.07 –9.69 –8.54 –9.80

NICS calculations on ghost atoms placed at varying distanc- 8.32 7.41 –7.37 –7.69 6.82 –6.85 O O O O O 3.94 –6.63 O es above the COT core agreed with this observation, giving 5.15 4.47 –6.33 –6.91 –10.16 an exponential relationship between distance and NICS val- –9.80 ue. NICS values were also calculated for varying points in O O O the plane and above the plane of the tetramer, as well as in 11 201 202 D4h C2v C2v between two sheets of the tetramer. The NICS values above –7.84 –7.78 O O –9.56 –9.59 –7.41 –7.19 the zinc atoms were found to be negative (diatropic mag- –8.28 –8.02 –8.46 –10.53 –6.82 –10.32 –6.66 –8.62 netic effect) for small distances. Increasing the distance to –8.47 –9.89 –10.19 –10.06 6.83 –7.37 6.55 O O the porphyrin sheet, the NICS value would grow rapidly to O 3.97 O –6.84 3.79 D6h positive values (paratropic magnetic effect) and slowly de- –8.25 –8.41 crease again. These results agree well with the experimen- –7.78 O –9.53 O tal data. In contrast, the NICS values calculated in between 203 –8.40 204 –10.47 two porphyrin sheets do not account well for the experi- D2h C2v mental data, presumably due to dynamic motion and deformation processes of the complexes. –7.85 O –9.59 O –7.14 –7.10 63 –8.49 D2h –9.39 In 2011, Minaev, Baryshnikov and Minaeva performed –6.67 –5.70 –8.61 –8.83 a DFT study [with optimization at the B3LYP/6-31G(d) lev- 6.57 9.23 O 3.83 O O O el] on many of the tetraoxa[8]circulenes synthesized by 5.99 Christensen and Pittelkow in 2010, together with one of Ra- O –11.91 thore’s tetraoxa[8]circulenes from 2004. The calculations O –9.40 O reproduced reasonably the UV/Vis and IR spectra of these 50 C2v 65b compounds. The following year, Pittelkow collaborated with D4h D4h these authors to publish a DFT study on the benzoquinone Figure 12 NICS values of differently annulated tetraoxa[8]circulenes. and naphthoquinone circulenes, arriving at good agree- NICS(0) values are presented in bold font and NICS(1) in regular font65 ment between simulation and experiment for the vibra- tional modes of these compounds.64 In further theoretical studies, in collaboration with Salcedo and Pittelkow, the lo- the thiophene subunits hints at an aromatic π-system, with cal aromatic and antiaromatic character of different tetra- somewhat reduced aromaticity compared to thiophene it- oxa[8]circulene systems was investigated by NICS indices.65 self (–10.2). The NICS(0) and NICS(1) values presented in Figure 12 were To address the overall magnetic current in hetero[8]cir- calculated by the B3LYP/6-311+G(d,p) method. culenes, NICS and gauge-including magnetically induced The positive NICS(0) values of the COT cores of the tetra- currents (GIMIC) calculations (at the B3LYP/TZVP level) oxa[8]circulenes ranged from 6.55 to 9.23, suggesting an- were conducted by Minaev and co-workers in 2014.67 The

tiaromaticity. By annulating benzenes, the antiaromatic GIMIC calculations allow for an estimation of the overall Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. character seems to be decreased. Attaching bicycloalkanes ring current strengths where positive values indicate over- conversely led to larger values. Overall, the COT cores exhib- all aromatic, and negative values indicate overall antiaro- it relatively small NICS values when compared to the stan- matic ring current. Benzene, as a typical aromatic com- dard D4h COT with an NICS(0) value of 30.1 at the B3LYP/6- pound, was calculated to have a total ring current of +11.8 31 G* level. The naphthalene and benzene moieties in the nA T–1 while antiaromatic cyclobutadiene featured a value tetraoxa[8]circulene feature NICS values comparable to of –19.9 nA T–1. Non-aromatic cyclohexane was calculated those of benzene and naphthalene themselves. A significant to have a total ring current of 0.2 nA T–1. The calculated difference was observed when comparing the NICS values global ring current strengths (Itot) of hetero[8]circulenes of furan with those of the furan moieties within the circu- were found to be either slightly antiaromatic (negative Itot) lenes. The authors suggested this was due to conjugation of or non-aromatic (very small Itot values around zero). An the furan ring with benzenes on each side, delocalizing the overall non-aromatic system was indicated by the similar furan π-electron system into the neighboring rings.65 size of the NICS values of the benzene, furan, and pyrrole Nenajdenko, Antipin and co-workers published the subunits and the COT core, which might cancel out. It has NICS(1) values of sulflower in 2008.66 The COT core of this been determined that the hetero[8]circulenes with one to compound gave a positive NICS(1) value of 2.4, indicating four nitrogen atoms experience a decrease in the numerical weak magnetic antiaromaticity. The negative value (–7.1) of value of the total ring current strength with an increasing –1 amount of nitrogen atoms (1 × N with Itot = –3.1 nA T and –1 4 × N with Itot = –0.5 nA T ). Azatrioxa[8]circulene displays

Syn lett T. Hensel et al. Account

a higher total ring current than tetraoxa[8]circulene (Itot = O 2– O O 2+ –2.9 –8.8 –9.9 –1 –9.0 –9.2 –18.2 –2.1 nA T ). In conclusion, tetraoxa-, azatrioxa-, and diaza- –2.4 –16.1 –20.9 –21.2 –22.1 –47.7 dioxa[8]circulene can be considered to be overall slightly –15.2 8.4 2.6 O O O O O O antiaromatic according to GIMIC calculations. One com- –37.0 20.9 3.2 pound, the tetraselenotetrathia[8]circulene, featured a –1 small positive total ring current of 0.6 nA T , making it O O O non-aromatic. Other heterocyclic [8]circulenes also exhibit- 112– 11 112+ ed non-aromaticity, but with small negative total ring cur- H H H N 2–N N 2+ –1 –5.4 –11.2 –19.3 rents, for example, triazamonooxa[8]circulene (–0.6 nA T ), –8.7 –9.1 –23.8 –7.6 –22.0 –44.9 tetraaza[8]circulene (–0.5 nA T–1) and sulflower (–0.2 nA T–1).67 –21.8 –22.5 –63.2 –2.5 –14.9 –8.8 8.3 –11.0 9.23 In a recent review, Baryshnikov, Minaev and Minaeva pre- O –1.8 –36.5 O O –16.1 20.6 O O –23.5 5.99 O

–8.8 –9.4 –12.6 sented experimental and theoretical data on the electronic –2.8 –8.7 –9.7 –20.7 –22.6 –33.0 68 –2.2 –15.9 –20.1 structure, aromaticity and spectra of hetero[8]circulenes. O O O 6b,34 In our recent work on azatrioxa[8]circulenes and di- 122– 12 122+ azadioxa[8]circulenes,6c we addressed the question of aro- N 2– N N 2+ maticity and antiaromaticity in the benzene, furan and COT –4.0 –10.6 –20.1 –8.5 –9.1 –21.2 –5.4 –21.0 –46.4 subunits via geometry optimizations and NICS calculations. –21.7 –22.8 –56.6 Geometries were obtained in B3LYP/6-31+G(d) calculations –14.5 –2.4 8.6 –8.6 14.7 –12.6 O –35.4 –2.1 O O 20.9 –16.0 O O 32.5 –27.4 O and employed in NICS(0) and NICS(1) calculations at the B3LYP/6-311+G(d,p) level of theory. The studied molecules in their oxidized and reduced forms are presented in Figure N N N

13, along with the respective NICS(0) and NICS(1) values. 2052– 205 2052+ The positive NICS values concerning the planar COT core in Figure 13 NICS values of tetraoxa-, azatrioxa- and diazadioxa[8]circu- the neutral forms of tetraoxa- 11, azatrioxa- 12 and diaza- lenes, including their doubly reduced and doubly oxidized derivatives. dioxa[8]circulene 205 are almost identical and suggest a NICS(0) values are presented in bold font and NICS(1) values in regular magnetic antiaromatic character. The benzene, furan and font6b,c pyrrole rings exhibit aromatic character with negative NICS values, in accordance with our experimental data. Curious- Nishinaga and co-workers recently published a study on ly, the NICS values of the doubly oxidized tetraoxa[8]circu- the aromaticity and antiaromaticity of the compounds pre- lene 112+ indicate a weakening of the antiaromaticity of the sented in Figure 14 (the syntheses of these compounds are COT core. Azatrioxa[8]circulene 122+ experiences signifi- described in Scheme 33).49 Their study highlighted different cantly smaller NICS(1) values, while the NICS(0) values are combinations of ortho-annulated aromatic compounds in slightly larger; diazadioxa[8]circulene 2052+ features sig- order to obtain COT structures of varying geometries (see nificantly larger NICS(0) and NICS(1) values. In the case of Figure 4). Optimizations at the B3LYP/6-31G(d,p) level de- the doubly negative charged species, the large negative val- termined the most stable conformer of dithiophene COT ues hint at an aromatic COT core. The bond length fluctua- 161 to be almost completely planar (C2v structure), in con-

tions were found to be significantly lower for the aromatic trast to the slightly bent structures of tetrathiophene COT Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. doubly reduced species. It could be argued, that the ob- 151 and significantly bent fluorene COT 207. The COT core served ring-current effect in the COT core arises solely from of 161 exhibited very small deviations concerning the inner the combined ring-current effects of the linked benzenes.6b angles in the optimized structures (133.2° to 136.8°) com-

However, NICS calculations of a ghost atom placed next to a pared to the ideal D4h octagon with angles of 135°. Com- benzene or next to two benzenes, with distances identical pound 206, having a deformed COT core, experienced larger to those in tetraoxa[8]circulene 11, revealed values of about deviations (124.0° to 143.5°). The simulated X-ray data cor- 1 and 2, respectively. A dummy atom surrounded by four responded well with the experimental values. Interestingly, equiplanar benzenes should yield a value of up to 4, in con- the experimental data of dithiophene-COT 161 showed two trast to the values above 8 calculated for the neutral hete- crystallographically independent conformers, one slightly ro[8]circulenes displayed in Figure 13. bent (shorter intermolecular C–H contacts caused by crystal packing forces) and the other planar. DFT calculations in the form of NICS values, concerning the dithiophene com-

pound 161, showed higher antiaromaticity (80% of D4h COT)

than tetrathiophene compound 151 (70% of D4h COT). It was assumed that the difference in antiaromaticity was due to the higher annulation of 151 with aromatic molecules, reducing the overall antiaromaticity of the COT core. More- over, the magnetic antiaromatic character and planarity of

Syn lett T. Hensel et al. Account the COT, demonstrated by the NICS values, decreased in the are presented in Figure 15. Similar to the aza- and following order: dithiophene-COT 161 > tetrathiophene- oxa[8]circulenes, the benzene, thiophene and selenophene COT 151 > phenylene-COT 206 > fluorene-COT 207. Anoth- rings were aromatic, as indicated by the obtained negative er indication of the antiaromatic character would be a nar- NICS values (–5.9 to –10.3). The central COT in tetrathia- row HOMO–LUMO gap. However, the increased antiaromat- 133 and tetraselena[8]circulene 134 exhibited positive NICS ic character of dithiophene 161 compared to tetrathio- values of 7.0 and 8.2, respectively, implying an antiaromatic phene 151 did not result in a smaller HOMO–LUMO gap, as character. The small value of 2.3 in the central COT of tet- UV/Vis spectra and CV studies exhibited similar values for raphenylene 131 most likely arose from the magnetic effect both compounds. Phenylene-COT 206 and fluorene-COT of the four benzene moieties surrounding it. It was further 207 were found, by UV/Vis spectroscopy and cyclic voltam- observed that the four compounds with only two sulfur metry, to have a larger HOMO–LUMO gap, consistent with (174, 208) or two selena bridges (176, 209), in general, fea- the calculated lower antiaromaticity. To determine the ture lowered NICS values. magnetic ring-current effects of the COT core experimen- MeO OMe MeO OMe tally, Nishinaga and co-workers recorded proton NMR spec- S Se a tra and found upfield shifts for the signals due to protons H MeO –8.9 OMe MeO –7.9 OMe –10.3 –9.3 and Hb, compared to those in cyclooctatriene 160 (Figure 14). The differences in the upfield shifts appeared to concur S 7.0 S Se 8.2 Se with the obtained NICS values, as protons Ha and Hb of dith- MeO OMe MeO OMe iophene COT 161 exhibited the highest upfield shifts and S Se MeO OMe MeO OMe those protons of fluorene-COT 207 the lowest. The dia- 133 134 tropic ring current of the thiophene and benzene groups appeared to weaken the influence of the magnetic ring cur- MeO OMe MeO OMe rent on proton Ha. The recorded crystal structures exhibited MeO OMe MeO OMe –9.9 –9.8 short distances between the thiophene protons and the Se COT unit between neighboring molecules. For this reason, S 6.1 –7.0 S Se 5.7 –6.5 solid state NMR analysis was conducted by Nishinaga et al. MeO OMe MeO OMe Their calculations predicted a large downfield shift of MeO OMe MeO OMe around 3.2–3.5 ppm. The actual recorded solid state NMR 208 209 45,49 data, however, revealed a signal shift of only 0.6 ppm. MeO OMe

MeO OMe S 4.41 5.94 –10.3 Hb Hb 4.71 6.73 2.3 S S Ha Ha OTMS 17.4 21.1 44.8 51.0 MeO OMe S S S S S S MeO OMe 131 S S TMS S Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. 151 161 160 –7.8 –7.6

–5.9 S 6.8 –6.6 S Se 6.5 Se 4.61 5.68 b b H H D4h 4.74 5.90 Ha Ha 174 176 13.8 8.6 26.6 32.5 19.5 62.5 Figure 15 NICS(0) values of tetraseleno- and tetrathia[8]circulene and related compounds50

206 207 Nguyen et al. recently investigated different hetero[8]circulenes with oxygen, nitrogen, selenium and sulfur Figure 14 NICS(0) and NICS(1) values and experimental chemical shifts of the COT protons obtained by Iyoda and Nishinaga45,49 bridges by DFT calculations. They carried out geometry optimizations at the B3LYP/6-31G(d,p) level of theory. These optimizations displayed a bond-length increase of the order Wong’s tetrathia- and tetraselena[8]circulenes, pub- C–O ~ C–N < C–S < C–Se. As a result, the tetraoxa[8]circu- lished in 2014, were also subjected to NICS calculations at lene, tetraaza[8]circulene and tetrathia[8]circulene feature the B3LYP/6-311+G(d,p) level of theory.50 The investigated planar structures, while tetraseleno[8]circulene was pre- compounds along with their corresponding NICS(0) values dicted to be slightly bent, as confirmed by Wong et al. in

Syn lett T. Hensel et al. Account

2015. The calculated NICS(0) values of the COT core de- (5) (a) Kanakaraju, R.; Kolandaivel, P. Int. J. Mol. Sci. 2002, 3, 777. crease with the increasing size of the heteroatom of the an- (b) Kwiatkowski, J. S.; Leszczynski, J.; Teca, I. J. Mol. Struct. 1997, nulated heterocycles (tetraoxa: 8.4 > tetraaza: 8.0 > tetra- 437, 451. (c) O’Sullivan, P. S.; Hameka, H. F. Chem. Phys. Lett. thia: 6.7 > tetraseleno: 4.1). The same trend was observed 1969, 4, 123. (6) (a) Mejlsøe, S. L.; Christensen, J. B. J. Heterocycl. Chem. 2014, 51, for the NICS(1) values, with the exception that the selenium 1051. (b) Nielsen, C. B.; Brock-Nannestad, T.; Hammershøj, P.; compounds exhibited the largest values. Overall, the calcu- Reenberg, T. K.; Schau-Magnussen, M.; Trpcevski, D.; Hensel, T.; lations indicated a magnetically antiaromatic COT core and Salcedo, R.; Baryshnikov, G. V.; Minaev, B. F.; Pittelkow, M. aromatic annulated five- and six-membered cycles, which Chem. Eur. J. 2013, 19, 3898. (c) Hensel, T.; Trpcevski, D.; Lind, is in accordance with many previous studies performed on C.; Grosjean, R.; Hammershøj, P.; Nielsen, C. B.; Brock-Nannes- hetero[8]circulenes.6b,c,34,44,45,50 The simulated UV/Vis spec- tad, T.; Nielsen, B. E.; Schau-Magnussen, M.; Minaev, B.; Baryshnikov, G. V.; Pittelkow, M. Chem. Eur. J. 2013, 19, 17097. tra corresponded well with the previous studies. (d) Feng, C.-N.; Kuo, M.-Y.; Wu, Y.-T. Angew. Chem. Int. Ed. 2013, 52, 7791. (e) Kumar, B.; King, B. T. J. Org. Chem. 2012, 77, 10617. 9 Conclusion and Outlook (f) Dadvand, A.; Cicoira, F.; Chernichenko, K. Y.; Balenkova, E. S.; Osuna, R. M.; Rosei, F.; Nenajdenko, V. G.; Perepichka, D. F. Chem. Commun. 2008, 5354. (g) Nakamura, Y.; Aratani, N.; In this account, we have presented an introduction to Shinokubo, H.; Takagi, A.; Kawai, T.; Matsumoto, T.; Yoon, Z. S.; the synthesis of [n]circulenes, hetero[8]circulenes and re- Kim, D. Y.; Ahn, T. K.; Kim, D.; Muranaka, A.; Kobayashi, N.; Osuka, A. J. 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Chem. 2005, 70, 10113. cations of hetero[8]circulenes, for example as organic light- (13) Anthony, J. W.; Bideaux, R. A.; Bladh, K. W.; Nichols, M. C. Hand- emitting diodes or in DNA intercalation, highlight the im- book of Mineralogy - Volume V: Borates, Carbonates, Sulfates; portance of undertaking further investigations. Mineral Data Publishing: Tucson, 1990. (14) Shen, M.; Ignatyev, I. S.; Xie, Y.; Schaefer, H. F. J. Phys. Chem. 1993, 97, 3212. Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. Acknowledgment (15) Yamamoto, K.; Sonobe, H.; Matsubara, H.; Sato, M.; Okamoto, S.; Kitaura, K. Angew. Chem., Int. Ed. Engl. 1996, 35, 69. We kindly thank the Lundbeck Foundation, the Novo Nordisk Scholar- (16) (a) Miller, R. W.; Duncan, A. K.; Schneebeli, S. T.; Gray, D. L.; ship Programme, and the University of Copenhagen for the financial Whalley, A. C. Chem. Eur. J. 2014, 20, 3705. (b) Sakamoto, Y.; support. Suzuki, T. J. Am. Chem. Soc. 2013, 135, 14074. 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