SCIENCE CHINA Chemistry •INVITED REVIEWS• . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . August 2018 Vol.61 No.8: 993–1003 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .https://doi.org/10.1007/s11426-018-9328-8 Coronarenes: recent advances and perspectives on macrocyclic and supramolecular chemistry Mei-Xiang Wang* MOE Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China Received June 21, 2018; accepted July 9, 2018; published online July 17, 2018 Synthetic macrocyclic host molecules always play an essential role in the establishment and development of supramolecular chemistry. Along with the continuous interests in the study of classical macrocycles, recent decades have witnessed the emergence and rapid development of the chemistry and supramolecular chemistry of novel and functional macrocycles. Owing to their easy availability, a self-tunable V-shaped cavity resulted from 1,3-alternate conformation, and diversified electronic features steered by the interplay between heteroatom linkages and aromatic rings, heteracalixaromatics act as a type of versatile and powerful macrocyclic hosts in molecular recognition and fabrication of supramolecular systems. Very recently, by means of engineering the bond connectivity or the recombination of chemical bonds within heteracalixaromatics, we have devised coronarenes, a new generation of macrocycles. In this concise review, macrocyclic and supramolecular chemistry of coronarenes are summarized in the order of their syntheses, structural features, molecular recognition and self-assembly properties. In the last part of this article, personal perspectives on the study of macrocyclic and supramolecular chemistry will also be discussed. coronarenes, heteracalixaromatics, macrocycles, molecular recognition, non-covalent bond interactions Citation: Wang MX. Coronarenes: recent advances and perspectives on macrocyclic and supramolecular chemistry. Sci China Chem, 2018, 61: 993–1003, https://doi.org/10.1007/s11426-018-9328-8 1 Introduction Design and construction of novel and functional macrocyclic molecules are one of the central focuses of study in supramolecular science [1]. Tailor-made synthetic macrocycles offer not only the excellent model systems to study the nature of various non-covalent interactions but also the essential building units for the fabrication of sophisticated (supra) molecular structures, advanced materials and machinery systems. Furthermore, two- and three-dimensional macrocycles with well-defined cavities are unique molecular tools in highly selective synthesis and in the study of reaction mechanisms. For some 15 years, we and others have been establishing *Corresponding author (email: wangmx@mail.tsinghua.edu.cn) and developing the chemistry and supramolecular chemistry of heteracalixaromatics or heteroatom-bridged calix(het) arenes (Figure 1) [2–9]. The macrocyclic scaffolds of heteracalix[n]aromatics are constructed by a stepwise fragment coupling approach through efficient nucleophilic aromatic substitution reaction or transition metal catalyzed crosscoupling reaction using cheap and mostly commercially available starting materials. Some symmetric heteracalix[4] aromatics are easily synthesized from the reaction of 1,3phenylene diol and diamine derivatives with highly reactive 1,3-dihaloarenes in a one-pot reaction manner. Post-macrocyclic chemical manipulations enable the generation of various tailor-made functionalized heteracalixaromatics. Because of the dipole-diploe interaction, heteracalix[4] aromatics generally adopt 1,3-alternate conformation, yielding a V-shaped cavity or cleft [10]. The cavity size © Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018 . . . . . . . . . . . . . . . . . . . . . chem.scichina.com link.springer.com 994 .................... Wang Sci China Chem August (2018) Vol.61 No.8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994 Figure 2 Figure 1 General structure of heteracalixaromatics (color online). varies greatly depending on the electronic and steric effects of the aromatic and heteroatom building blocks. Most remarkably, the electronic feature of the macrocyclic cavity of a heteracalixaromatic ring is amenable to regulation due to the interplay between aromatic moieties and heteroatom linkages. The rational combinations of individual aromatic rings and heteroatoms lead therefore to the desired heteracalixaromatics with powerful and versatile capability in complexing selectively with metal ions, anions and electronneutral guest species [4–9]. To our delight, heteracalixaromacs have been shown to date by a number of research groups to have many applications ranging from molecular recognition and self-assembly, the fabrication of supramolecular materials and functional systems [9], to molecular tools in elucidation of the reaction mechanisms of high valent organocopper compounds [11–15]. To construct cylindroid cavities other than the V-shaped ones while remaining the salient advantages to tune electronic features and properties through the interplay between aromatic rings and heteroatoms, we have recently designed coronarenes, a novel class of macrocycles, based on the replacement of all meta arylenes within heteracalixaromatics with para ones [16,17]. Coronarenes are therefore referred to macrocycles which are composed of para arylenes and heteroatoms alternatively in a cyclic fashion (Figure 2). In recent years, we have systematically studied the synthesis and structure of coronarenes. Molecular recognition property of coronarenes has also been explored. In this article, research advances of the chemistry of coronarenes are summarized. I would also like to give my personal perspectives on macrocyclic and supramolecular chemistry by the end of the article. 2 Nomenclature of coronarenes According to nomenclature recommended by International Union of Pure and Applied Chemistry (IUPAC), coronarene compounds belong to cyclophanes and have very long names. Following the tradition of naming macrocycles, and based on the coronary conformation of the compounds (infra General structure of coronarenes (color online). vide) we suggest the name Xn-corona[n](het)arenes to describe the macrocycles that are composed of para-(het)arylenes and heteroatoms in an alternative manner. While the type and the number of linking heteroatoms are prefixed to corona, the bracketed number(s) followed by the name of (het)aromatic rings after corona indicate the aromatic components. O6-Corona[3]arene[3]tetrazine, for example, means a macrocycle consisting alternately of three phenylene units and three tetrazinylene units that are bridged by six oxygen atoms. 3 Synthesis of coronarenes The convenient and cost-effective accesses to diverse coronarenes are the prerequisite to the development of novel chemistry and supramolecular chemistry of coronarenes. We have established and developed several synthetic strategies ranging from one-pot de novo construction method, stepwise fragment coupling approach, macrocycle-to-macrocycle transformations, post-macrocyclization oxidation of sulfide linkages and functional group transformation. Based on these methods, a large number of novel and functionalized coronarenes of different macrocyclic ring sizes and electronic features have been synthesized. 3.1 De novo construction of coronarene macrocyclic rings Taking on the advantage of facile nucleophilic aromatic substitution reaction of 3,6-dichlorotetrazine 3 [18] with aromatic diols 1 and dithiols 2, we have established a very efficient one-pot reaction method to construct macrocyclic structure of oxygen- [16] and sulfur-linked coronarenes [17], respectively. Shown in Figure 3 are our first synthesis of oxygen and sulfur linked corona[3]arene[3]tetrazines 4 and 5. The following features of this synthetic method are worth addressing. First of all, the starting materials such as aromatic diols, dithiols and 3,6-chlorotetrazine are readily available either from commercial sources or from synthesis based on well-documented procedures [18]. No expensive catalysts, reagents and solvents are required. Second, the reaction conditions are very mild and operationally simple. The chemical yields are moderate to good. Consideration of 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . Wang Figure 3 Sci China Chem August (2018) Vol.61 No.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995 The one-pot reaction method for the synthesis of oxygen and sulfur linked corona[3]arene[3]tetrazines (color online). formation of six chemical bonds in synthesis, a chemical yield of 53% from one-pot synthesis means 90% efficiency in each single bond formation reaction. Preparation is also scalable. For instance, a gram scale synthesis of O6-corona [3]arene[3]tetrazine has been demonstrated. In addition, the method is general and applicable to not only simple 1,4dihydroxy and 1,4-dimercaptobenzene substrates but diols and dithiols derived from fused arenes as well. Thus, the employment of 1,5- and 2,6-naphthodiols [19], 4,4′-dihydrox-1,1′-biphenyl, 9H-fluorene-3,6-dithiol [17] in the synthesis, for example, led to the formation of corona[3] arene[3]tetrazines with varied cavity sizes. Furthermore, the use of pre-functionalized diols and dithiols enables the construction of multifunctional corona[6]arenes [17,19]. Moreover, tetrazine is transformable aromatic subunit amenable to inverse electron demand Diels-Alder reaction, offering a great opportunity for the synthesis of pyridazinebearing coronarenes (infra vide). The one-pot reaction has been successfully extended to the synthesis of corona[4]arene[2]tetrazines with mixed heteroatom bridges [20]. As illustrated in Figure 4, 4,4′-methyl-, oxy, thio- and sulfonyl-bridged diphenols and dibenzenethiols react with 3,6-dichlorotetrazines affords the corresponding corona[4]arene[2]tetrazines as the major products. It should be noted that, being different from the synthesis of corona[3]arene[3]tetrazines in which no larger macrocyclic ring analogs are isolated, some reactions depicted in Figure 4 gives low yields of corona[6]arene[3]tetrazines and even corona[8]arene[4]tetrazines. In comparison to corona[6]arenes, synthesis of corona[5] arenes appeared challenging [21]. After a serendipitous discovery of the macrocycle-to-macrocycle transformation of S6-corona[3]arene[3]arenes, infra vide, we have established a straightforward three-component reaction to prepare a number of corona[3]arene[2]tetrazines. In the presence of diisopropylethylamine (DIPEA), a mixture of 1,4-benzenedithiol 2, 3,6-dichlorotetrazine 3 and 4,4′-methylene-, propane-2,2-diyl-, thio- or sulfonyl-bridged dibenzenethiols 7 in a 1:2:1 ratio undergoes macrocyclization reaction to generate corona[5]arene products 10 (Figure 5). Except for sulfonecontaining macrocycle which was obtained in a low yield (11%), the rest three-component reactions give acceptable yields (41%–46%) [21]. Stepwise fragment coupling reaction provides another useful route to coronarenes [22–24]. One of the examples, which is depicted in Figure 6, is the synthesis of corona[4] arene[2]tetrazines that contain different combinations of nitrogen atom with O, S, SO2 and CH2. N,N-Bis(4-hydroxyphenyl)acetamide 11 undergoes two directional nucleophilic aromatic substitution reaction with 3,6-dichlorotetrazine 3 to afford linear tetramer intermediate 12 in 74% yield. Treatment of 11 with diols 6 or dithiols 7 and 11 in warm acetonitrile gives rise to the formation of corona[4] arene[2]tetrazines 13 [22]. 3.2 Synthesis of coronarenes from macrocycle-to-macrocycle transformations In an attempt to prepare corona[5]arenes by means of a stepwise fragment coupling route, we mistakenly mixed S6corona[3]arene[3]tetrazine with 4,4′-thiodibenzenethiol. Astonishingly, the reaction at −20 °C was found to yield S5corona[3]arene[2]tetrazine in 72% yield. Since S6-corona[3] arene[3]tetrazine is easily available, supra vide, the macro- 996 .................... Wang Sci China Chem Figure 4 Synthesis of corona[4]arene[2]tetrazines from one-pot reaction (color online). Figure 5 One-pot three-component reaction for the synthesis corona[3] arene[2]tetrazines (color online). August (2018) Vol.61 No.8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996 zine, we have established a powerful macrocycle-to-macrocycle transformation method to construct new coronarene scaffolds [17,25]. It is noteworthy that all tetrazine rings in corona[3]arene[3]tetrazines and corona[4]arene[2]tetrazines are capable of reacting effectively with enamines and norbornadiene, which are respectively electron-rich and highly strained dienophiles. Demonstrated in Figure 8 are the examples of the synthesis of oxygen and sulfur linked corona [3]arene[3]pyridazines 14 and 15 from [4+2] cycloaddition reaction of coronarenes 4 and 5 with enamines followed by deaminative aromatization [17,25]. Notably, the reaction of sulfur-bridged coronarenes 5 [17] proceeds more efficiently than that of oxygen atom linked analogs 4 [25], owing probably to different electronic effect between sulfur and oxygen on tetrazine ring. In addition to the ring transformation of aromatic subunits, selective oxidation of sulfide linkages constitutes another simple and efficient macrocycle-to-macrocycle method in the production of novel coronarenes [17,20]. Under controlled oxidation reaction conditions, sulfide is known to undergo selective oxidation to give sulfone and sulfoxide functionalities. As exemplified in Figure 9, in the presence of m-CPBA, (CH2)2,S4-corona[4]arene[2]pyridazine 15a is oxidized into (CH2)2,(SO2)4-corona[4]arene[2]pyridazine 16 while selective oxidation of diphenylsulfide moieties with Selectfluo yields S4,(SO)2-corona[4]arene[2]pyridazine 17 [20]. 3.3 Functional group transformations in the synthesis functionalized coronarenes In comparison to de novo synthesis and macrocycle-to- Figure 6 The fragment coupling approach to corona[4]arene[2]tetrazines (color online). Figure 7 Synthesis of corona[5]arenes from corona[6]arenes through macrocycle-to-macrocycle transformation (color online). cycle-to-macrocycle transformation of corona[6]arenes has been developed into a useful protocol to synthesize corona [5]arenes 10 (Figure 7) [21]. The driving force for the conversion of corona[6]arenes 5 into corona[5]arenes 10 is most probably duo to the higher thermodynamic stability of the later macrocycles than that of the former ones. The nature of dynamic covalent bond between sulfur and triazine, on the other hand, is attributed to account for the rapid reaction process. Tetrazine is viewed as an electron deficient heterodiene able to undergo inverse electron demand hetero-Diels-Alder reaction. Taking the advantage of unique reactivity of tetra- Figure 8 Synthesis of corona[3]arene[3]pyridazines from inverse electron demand Diels-Alder reaction of corona[3]arene[3]tetrazines (color online). 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . Wang Sci China Chem August (2018) Vol.61 No.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997 Figure 9 Synthesis of sulfone and sulphide linked corona[4]arene[2] pyridazines from selective oxidation of sulphide (color online). Figure 10 Synthesis of functionalized coronarenes via functional group transformations (color online). macrocycle transformation methods aforementioned, postmacrocyclization functional group transformation is a conceivably straightforward and practical means to fabricate coronarenes. Chemical manipulation of various functional groups introduced in the macrocyclic ring construction step would permit the generation of tailor-made functional coronarenes. Simple reduction of all ester groups in O6-corona [6]arene 18 for instance affords O6-corona[6]arene 19 with six hydroxymethyl groups which would provide a platform for further functionalizations [23] while saponification of O6[26] and S6-corona[3]arene[3]pyridazine 20 [26] followed by salification furnishes the water soluble coronarenes 21 (Figure 10). For example, O6-corona[3]arene[3]tetrazines give a nearly equilateral hexagon cavity with the average distances between centroids of two proximal aromatic rings and between centroids of two distal aromatic rings are around 4.61 to 4.63 Å and 9.21 to 9.26 Å, respectively (Figure 11(a)) [16]. Much larger isogonal hexagon cavities are observed on the other hand from O6-corona[3](1,1′-biphenyl)[3]tetrazines (Figure 11(b)) and O6-corona[3](9H-fluorene)[3]pyridazine (Figure 11(c)) [19]. Furthermore, the change of tetrazines by pyridazines in corona[6]arenes does not affect the size of macrocyclic cavity. This is important to engineer the macrocyclic hosts which have substantially different electronic feature but the same cavity size (infra vide). Moreover, the nature of the heteroatom linkages plays an important effect on the tuning of macrocyclic conformation. The replacement of oxygen atoms by sulfur atoms leads to the slight distortion and enlargement of hexagon cavities due to larger atomic radius of sulfur (Figure 11(d, e)) [17]. After exhaust oxidation of sulfide bridges, for instance, the resulting (SO2)6corona[3](9H-fluorene)[3]pyridazine produces a conformer in which almost all aromatic subunits are perpendicular to the plane defined by six sulfur atoms of bridging sulfones (Figure 11(f)) [17]. Finally, the bond lengths and bond angles indicate the formation of conjugation of bridging oxygen atoms with their neighboring electron-deficient heterocyclic ring rather than with the arene ring [16–20]. As depicted in Figure 12, all corona[5]arenes 10 form nearly similar regular pentagons with the mean side lengths ranging from 6.06 to 6.24 Å. All bridging atoms in corona[5] arenes locate nearly on the same plane. The angle (α) between two phenylenes varies from 100° to 114° depending on the nature of X, while the rest four internal angles are almost identical (100° to 104°) (Figure 12). Two tetrazine rings are procumbent on the plane, and p-phenylene rings, 4 Structure of coronarenes Almost all of the coronarenes obtained so far are crystalline compounds, and most of them give high quality single crystals from recrystallization, permitting X-ray diffraction analysis. X-ray molecular structures show that coronarenes adopt various coronary conformations in the crystalline state. Some interesting structural features are worth noting. First of all, as revealed by their X-ray molecular structures, all six bridging oxygen atoms in O6-corona[6]arenes which contain either tetrazine (Figure 11(a, b)) or pyridazine rings are located almost on the same plane [16]. In the case of sulfurlinked analogs, however, six sulfur atoms are hardly in the same plane [17]. Second, while three heterocyclic rings are procumbent on the plane, (substituted) benzenes, naphthalenes and biphenyl moieties tend be orthogonal to the plane (Figure 11(a–e)) [16,17]. In addition, corona[6]arenes yield approximately hexagon cavities, and the cavity sizes are dependent on the sizes of building (het)arylene components. 998 .................... Figure 11 Wang Sci China Chem August (2018) Vol.61 No.8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998 Some representative X-ray molecular structures of corona[6]arenes with top and side views. Substituents are hidden for clarity (color online). bulky substituents at 2,4-position, complicated proton and carbon resonance signals were observed at room temperature. With the increase of the probe temperature, the signals became gradually broadened, coalesced and well-resolved peaks (Figure 13) [16]. The VT NMR spectra indicate clearly the presence of a mixture of conformers in solution. They undergo very rapid interconversion at an elevated temperature in relative to the NMR time scale. Figure 12 X-ray molecular structures of corona[5]arenes with top and side views (color online). especially, the diethyl terephthalate moiety or the phenylene between two tetrazine rings tend to be orthogonal to the plane. The cavity sizes, as defined by the distance (d) between the centroid of terephthalate ring and heteroatome or methylene carbon (X), decreased from 9.29–9.82 to 9.00–9.08 Å and 8.74 Å along the change of X from sulfur to carbon and then to oxygen, indicating a fine-tuning effect on the cavity sizes by the bridging elements [21]. In solution, most of the corona[6]arenes and corona[5] arenes give one simple set of proton and carbon resonance signals at room temperature in their 1H and 13C NMR spectra, respectively [17,19,20,22–24]. However, in the case of oxygen-linked corona[3]arene[3]tetrazines [16] and corona [3]arene[3]pyridazines [25] in which phenylene units contain 5 Electronic properties spectral and electrochemical All tetrazine-bearing coronarenes are red-colored compounds, and their electronic absorption spectra exhibit two absorption bands at λmax=320–337 nm and at λmax=518– 535 nm with molar extinction coefficients (ε) being around 104 and 103 mol−1 cm−1, respectively. The strong absorption bands at a short wavelength region correspond to π→π* transitions while the low energy absorptions are attributable to n→π* transitions of a tetrazine component [16,17,19,20,22]. Under irradiation, O6-corona[3]arene[3] tetrazines display a fluorescence emission band at 558– 584 nm in dichloromethane (DCM). Due to probably the heavy atom effect, very weak or virtually no fluorescence 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . Wang Sci China Chem August (2018) Vol.61 No.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999 Figure 13 Partial variable temperature 1H NMR (a) and 13C NMR (b, c (expanded)) spectra of O6-corona[3]arene[3]tetrazine derived from 2,6-dibromo1,4-dihydroxybenzene in d6-DMSO. emission was detected for sulfur-linked macrocycle analogs [16,22]. Most of the oxygen- and sulfur-linked corona[3]arene[3] tetrazines gave a very similar electrochemical response in their cyclic voltammograms (CV), showing a characteristic reversible redox couple due to one electron reduction and oxidation of the tetrazine moiety [16,17]. The half-wave reduction potentials measured by CV and differential pulse voltammetry (DPV) are in the range of −792 to −1135 mV versus Fc/Fc+. Notably, S6-coronacorona[3]arene[3]tetrazine, which is derived from diethyl 2,5-dimercaptoterephthalates, proceeded through a sequential one-electron redox process at −939, −987 and −1194 mV while S6-corona[3]arene[3]tetrazine experienced one-electron redox simultaneously with two tetrazine rings at −990 mV followed by redox for the last tetrazine at −1130 mV [17]. All corona[3]arene[2]tetrazines, on the other hand, proceed reversibly through a sequential one-electron redox process, giving E1/2(1) from −978 to −1085 mV and E1/2(2) from −1083 to −1196 mV [21]. The occurrence of electronic communication between the three or two equivalent tetrazine redox centers within the corona[6] arenes and corona[5]arene macrocycles is due to probably electron sharing through space. It should be pointed out that all S6-corona[3]arene[3]pyridazine macrocycles are inert toward electrochemical reduction in the range of −600 to −2200 mV. However, after the sulfide linkages were oxidized, the resulting sulfone-bridged corona[3]arene[3]pyridazines gave the half-wave reduction potentials ranging from −1365 to −1848 mV [17]. It has also been observed that the presence of stronger electron-withdrawing groups on the phenylene rings lowered the reduction potentials of coronarenes [16,17]. It is worth addressing that the substantial difference of redox potentials suggests the formation of a library of coronarenes of varied electronic features. They can be used therefore as hosts to interact selectively with various electron-deficient and electron-rich guest species. 6 Molecular recognition The easy availability, cylindroid cavity of different geometries and sizes, and tunable electronic feature render coronarenes useful synthetic macrocycles in the study molecular recognition and self-assembly. Although the investigation into the applications is still in the early stage, examples reported in literature have demonstrated indeed that coronarenes are versatile hosts to form complexes with cations, anions and electron-neutral organic molecules. 6.1 Anion recognition In the first publication of coronarene, we reported the observation of complexation of O6-corona[3]arene[3]tetrazine with chloride. Owing to its electron deficiency, each tetrazine in O6-corona[3]arene[3]tetrazine is able to form complex with chloride by mainly the typical anion-π interaction. Evidenced by X-ray molecular structure, the chloride is located above the centroid of tetrazine ring with the distance (dCl…tetrazine centroid) being shorter than the van der Waals radius. In addition to attractive anion-π interaction, the C–H bonds of phenylene moieties also form non-conventional hydrogen bonds with chloride [16]. Very recently, N2,O4-corona[4]arene[2]tetrazine 13 has been shown to form complexes with anions of varied geo- 1000 . ................... Wang Sci China Chem August (2018) Vol.61 No.8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000 metries and shapes yielding diverse assembled structures in the solid state [22]. Illustrated in Figure 14 is the [13⋅Br−] complex structure. Bromide anion (Br1) locates over the center of the tetrazine (T1) ring, and the distance of Br1 to the plane of tetrazine (T1) (dBr1-plane=3.464 Å) is short. Noticeably, the tetrazine ring in complexation with bromide adopts a pinched boat conformation with the dihedral angle of planeN-N-N-N and planeC-N-N being 16.2°. The deformation of a planar aromatic ring to a flattened boat conformation accords the typical attractive anion-π interactions predicted by theoretical calculations [27]. Besides, Br1 also has a short contact (dBr1-plane=3.357 Å) to tetrazine (T2) ring from the neighboring coroanarene. The bromide anion (Br1) is actually sandwiched by two tetrazine (T1 and T2) rings due to dual anion-π interactions. To avoid steric hindrance coming from the macrocyclic backbone, these two tetrazine rings are not face-to-face paralleled. Instead, they open up slightly to give a V-shaped alignment, with the nearest and longest distances of T1 and T2 being 5.999 (dC2-C18) and 7.080 Å (dC1-C17), respectively. Evidently, directed by dual anion-π interactions, bromide anions act as a gluing component to assemble corona[4]arene[2]tetrazines into one-dimensional structure (Figure 14, right column). Very similar sandwiched anion-π complexation and assembled structures were observed for the complexes of 13 with spherical iodide (I−), linear thiocyanate (NCS−) and tetrahedral perchlorate (ClO4−) [22]. When naphthalene-1,5-disulfonate, an organic bis-anionic species, was interacted with corona[4]arene[2]tetrazine 13, each sulfonate group complexes with one tetrazine ring due to the typical anion-π interactions. As a result, naphthalene1,5-disulfonate looks like encapsulated by two coronarene molecules (Figure 15). Each complexed capsule then assembles into a linear structure through dimethyl sulfoxide (DMSO) solvent molecules which associate with the other tetrazine ring of coronarene via lone-pair electron-π interaction [28,29] (Figure 15). In contrast to corona[3]arene[3]tetrazines, corona[3]arene[3] pyridazines contain electron-rich cavity and they are able to recognize a large number of cation guests. Oxygen- and sulfur-bridged corona[3]arene[3]pyridazines form 1:1 complexes selectively with aliphatic and aromatic mono-ammonium and di-ammonium cations in acetonitrile. The binding constants, which are measured by means of UV-vis and 1H NMR titration, are in a wide range of 102 to 105 M−1 based on data depending on the structure of cation species [17,22,25,30,31]. Using S6-corona[3]arene[3]pyridazine as a model macrocyclic host, non-covalent bond interactions between coronarenes with ammonium cations has been investigated systematically employing isothermal titration calorimetry [30]. It has been found that the presence of a benzyl group in alkyl(trimethyl)ammoniums enhanced the hostguest complexation. On the other hand, while moderate bonding was also observed to acetyl choline, the strength of binding with 1,4-dibenzyl-1,4-diazabicyclo[2.2.2]octane1,4-diium was as high as up to (1.48±0.11)×105 M−1. The variation of monocation to dication, viz. the introduction of one more N-benzyl group to 1,4-dibenzyl-1,4-diazabicyclo [2.2.2]octane, resulted in a nearly 100-fold increase of binding. The host also shows stronger affinity to heteroaromatic dications than to simple aliphatic ammonium cations. It is important to note that N-alkyl ammonium and diammonium cations of relatively large volumes interacted strongly with the host owing to most probably the large cavity of the macrocyclic host. The thermodynamics on the basis of ITC titrations reveal that both favorable enthalpy (∆H) and entropy (T∆S) effects contribute to the free energy gain in all host-guest binding processes in solution, although some processes are driven mainly by the enthalpy effect whereas in other cases the entropy effect plays a dominant role [31]. It is significant that water soluble coronarenes form com- Figure 14 X-ray molecular structure of the complex between coronarene 13 and n-Bu4NBr. Cations and solvent molecules are omitted for clarity (color online). Figure 15 X-ray molecular structure of complex between coronarene 13 and tetrabutylammonium naphthalene-1,5-disulfonate. Cation and solvent molecules are omitted for clarity (color online). 6.2 Cation recognition 9. . . . . . . . . . . . . . . . . . . . . . . . . . . Wang Sci China Chem plexes selectively with ammonium cations in pure water. For example, both sulfur and oxygen-linked corona[3]arene[3] pyridazines 21 (X=O, S) are able to complex paraquat in a 1:1 stoichiometric ratio with the binding constant up to (2.67±0.21)×104 M−1 [17,25,26]. The effective binding of S6corona[3]arene[3]pyridazine 21 (X=S) with bisquaternary ammonium species has been used successfully in the fabrication of a supra-amphiphile which undergoes self-assembly to give micellar aggregates in water [30]. Interestingly, different supramolecular motifs have been observed for the host-guest complexes between electron-rich coronarenes and ammonium cations depending on the structure of guests. As revealed by the X-ray molecular structure, 1-methyl-1,3,5,7-tetraazaadamantan-1-ium [17] and 6,7-dihydrodipyrido[1,2a:2′,1′-c]pyrazine-5,8-diium [31] are included by one and two S6-corona[3]arene[3]pyridazine in the solid state. One of the fascinating examples is the formation of a pseudorotaxane structure between macrocyclic host and 1,4-dibenzyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium in which the bulky bridged bicycle dication acts as the threading component [17] (Figure 16). Based on the X-ray molecular structures, there are multiple noncovalent bond interactions such as non-conventional hydrogen bonds, π/π stacking and C–H/π interactions between coronarenes and ammonium cations in the complexes [17,25,26,31]. 6.3 Recognition of organic molecules In addition to anion and cation species, some electron-neutral organic compounds also form inclusion complexes with coronarenes. Among the examples of macrocycle-organic molecule interactions [19,23–25], selective recognition of coronarenes with fullerenes C60 and C70 is especially worth addressing. In contrast to various heteracalixaromatics [5,32], functionalized O6-corona[6]renes [23,24] and corona[3]arene[3] pyridazines [19] which all bind strongly with C60 and C70 with virtually no selectivity, intriguingly, O6-corona[3]arene [3]tetrazines complex only with C70 [19]. The association Figure 16 X-ray molecular structure of complex between coronarene and 1,4-dibenzyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium hexafluorophosphate. Cation and solvent molecules are omitted for clarity (color online). August (2018) Vol.61 No.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 constant (K1:1), which was measured in toluene by means of fluorescence titration, is up to (3.96±0.08)×104 M−1. Although the high selectivity of tetrazine-bearing corona[6] arenes in fullerene recognition has been ascribed to an electronic rather than steric effect of the hosts, further study is needed [19]. 7 Summary As a new type of synthetic macrocycles, coronarenes enjoy first of all the great structural diversity. Combination of para(het)arylenes and hetereoatoms should generate in theory numerous coronarene macrocycles. Coronarenes are also subject to functionalization both on the aromatic rings and heteroatom linkages, further expanding the structural diversity. Besides, the use of different numbers and the structurally-varied (het)arylene units permits the construction of macrocyclic cavities of tunable shapes and sizes. Furthermore, the incorporation of various (het)aromatic rings and hetereoatoms gives rise to an array of coronarenes of different electronic features. Therefore, coronarenes are applicable in molecular recognition towards both electronneutral organic molecules, positively and negatively charged guest species. Moreover, coronarenes are readily accessible by a number of efficient and straightforward synthetic methods. It is believed that the easy availability, tunable macrocyclic cavity structures and electronic features, versatile complexation property would render coronarenes very useful macrocyclic host molecules. 8 Perspectives on macrocyclic and supramolecular chemistry Supramolecular chemistry, an appealing and provoking term introduced by Lehn [1] to describe the chemistry of molecular assemblies and of the intermolecular bond, has become a popular and vigorous discipline since Pedersen’s landmark work on crown ethers more than 50 years ago. Evolved from chemistry and now as the indispensable part of chemical, biological and material sciences, the hard-core of supramolecular chemistry studies the structure, property and transformation of matters in various systems with the focus on non-covalent interactions of molecules. Despite tremendous achievements, the future accelerating and sustainable development of supramolecular chemistry depends mainly on the exploration, comprehension and manipulation of noncovalent bond interactions at various levels in artificial and biological systems. In addition, it is highly desirable but still extremely challenging to fabricate assembled structures, devices and machinery systems with sophisticated functions such as solar energy harvest and storage and conversion, 1002 . ................... Sci China Chem August (2018) Vol.61 No.8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002 information processing, target-specific diagnose and therapy, and catalysis. Furthermore, one of the ultimate and formidable tasks is the construction of artificial cells and mimetic living systems, the Holy Grail in supramolecular chemistry [33]. Among various research strategies and approaches to tackle the problems in question, tailor-made synthetic macrocycles offer great opportunities and powerful solutions as they can give not only the excellent model systems to study the nature of various non-covalent interactions but also the essential building units for sophisticated functional assemblies. This has been manifested extraordinarily by the early studies on the privileged crown ethers [34], cryptands [35], spherands [36], cyclodextrin derivatives [37] and calixarenes [38], which generated many, if not all, fundamental concepts leading to the foundation of supramolecular chemistry [1]. In the following decades, the functional macrocycles such as cucurbiturils [39], calixpyrroles [40], heteracalixaromatics [3–9], cycloparaphenylenes (CPPs) [41] and pillar[n]arenes [42], among many others, provides driving forces to promote the major advances of the field. Evidently, one of the salient advantages of macrocycle strategy is the designability of macrocyclic hosts or building blocks. Admittedly, however, there are no universal synthetic hosts in terms of application, as the function of a given macrocycle is destined by its intrinsic structure. It is therefore always important and exciting to design the structure of and to establish facile synthetic methods for novel and multifunctional macrocycles. Pleasingly, a number of new and interesting macrocyclic scaffolds have been designed very recently. For example, in addition to heteracalixaromatics [3–9], CPPs [41,43], pillararenes [42] and coronarenes, the Texas-sized molecular box [44] and various ExBoxs [1b], cyanostar [45], triptycene-based macrocycles [46], naphthalene-based tub[n]arenes [47] and biphen[n]arenes [48] have been reported as powerful macrocyclic host molecules. With the advent of new and efficient methods in chemical synthesis, emergence of more synthetic macrocycles can be expected in future. In parallel to create novel and functional macrocycles, exploration of new noncovalent bond interactions and supramolecular motifs is always of significance. A very recent and noteworthy example of burgeoning non-covalent interactions is anion/π interactions, the attractive interactions between negatively charged species and electron-deficient aromatic rings [49]. There are two general types of anion/π interaction motifs; a typical anion/π interaction indicates the attraction of an anion species to the centroid of an aromatic ring while the weak σ-interactions describe the contacting modes in which an anion is located over the periphery of an aromatic ring. Using synthetic macrocycles, the generality, binding strength and structures of interactions of the electron-deficient aromatic s-triazine with various anion species of different geometries and shapes have been established on the basis of the formation of host-guest complexes in solution, gas phase and solid state [50]. The anion/π interactions have been recognized currently as a new kind of non-covalent bond interactions and they have been finding applications in molecular recognition and self-assembly, catalysis, and in the regulation of small molecule/protein interactions and in the fabrication of functional materials [51]. It is believed that the use of designed synthetic receptors as molecular tools along with advanced analytical methods and powerful computing technology would fruitfully result in the discovery of new types of non-covalent bond interactions which would undoubtedly promote the further advances of supramolecular chemistry. One of the aims of supramolecular chemistry is to produce property-orientated molecular assemblies and materials. Indeed, supramolecular chemistry has been becoming a unique method to obtain hierarchically assembled structures and complex molecular systems, chemical sensors and optoelectronic devices, and stimuli-responsive and smart materials. However, in comparison to the sophistication of chemical synthesis based on chemical bond theory, controllable molecular self-assembly by means of non-covalent bond interactions is still in its infancy. On the other hand, supramolecular chemistry becomes integrated with chemical biology and synthetic biology. Based on molecular recognition, selective or specific interactions of an active organic probe or dye molecule with targeting nucleic acids and proteins may trigger biological events or show bio-images, respectively, enabling the elucidation of biological networks and signal transduction. Strong and highly selective interactions of molecules with cells and biological systems lay the foundation of drug discovery, facilitating the discovery of either drugable receptors or lead compounds. Successful gene delivery and the controlled drug-release systems are also mainly dependent on the construction of dynamic supramolecular systems, which are sensitive and responsive to the fine tuning of physiological conditions. The prospective applications of supramolecular chemistry in materials and life science would be achieved by using rationally designed functional macrocycles including coronarenes and following the comprehension and the elaboration of the control of noncovalent bond interactions in multicomponent systems. Wang Acknowledgements This work was supported by the National Natural Science Foundation of China (21732004, 21421064, 91427301, 21132005) and Tsinghua University. I am indebted to talented research students and postdoctoral fellows, whose names can be found in references, for their great contributions to the project of macrocyclic and supramolecular chemistry. Conflict of interest The author declares no conflict of interest. 1 (a) Lehn J-M, Atwood JL, Davies JED, MacNicol DD, Vögtle F. Comprehensive Supramolecular Chemistry. Oxford: Pergamon, 1996; (b) Liu Z, Nalluri SKM, Stoddart JF. Chem Soc Rev, 2017, 46: 2459– 2478 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . 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