Open AccessCCS ChemistryCOMMUNICATION18 May 2022Construction and Functionalization of Highly Strained N-Doped Zigzag Hydrocarbon Belts Ming Xie, Shuo Tong and Mei-Xiang Wang Ming Xie MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 Google Scholar More articles by this author , Shuo Tong MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 Google Scholar More articles by this author and Mei-Xiang Wang *Corresponding author: E-mail Address: [email protected] MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202008 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Recent years have witnessed breakthroughs in the study of zigzag hydrocarbon belts. However, the synthesis of heterocycle-containing zigzag molecular belts remains very rare and challenging despite their interesting structures and potential applications in chemistry and materials science. Here, we report the expeditious construction of a highly strained belt[4]arene[4](1,4-dihydropyridine) structure using the fjords-stitching strategy. The synthesis comprised four-fold abnormal m-bromination of four N-pivaloylaniline units and Pd2(dba)3/4-Me2NC6H4PtBu2-catalyzed intramolecular C–N bond-forming reactions. Subsequent functionalization through N-arylations produced a variety of tetraza-embedded octahydrobelt[8]arenes. Further oxidation of p-methoxyphenyl-substituted belt[4]arene[4](1,4-dihydropyridine) with Ag[Al(OtBuF)4] yielded a singlet diradical dication N-doped zigzag belt. Download figure Download PowerPoint Introduction Zigzag hydrocarbon belts such as belt[n]arenes or [n]cyclacenes A (Figure 1) are composed of linearly fused benzene rings in a macrocyclic fashion. They initially appeared in the literature more than six decades ago as fictional molecules.1 Later, in the 1980s and 1990s, they were proposed as synthetic targets, along with partly hydrogenated derivatives, including collarenes B and beltenes C (Figure 1).2 Despite their unique structures, tantalizing physical properties, and potential applications in materials science and nanotechnology, the synthesis of these double-stranded macrocycles remains challenging.2–5 One of the insurmountable hurdles is the ramp-up of macrocyclic strain during the construction of belt structures.6 The presumed open-shell electronic characteristics of the fully conjugated structures7 might also impose difficulty in making them. The breakthroughs in the synthesis have been reported very recently.8–15 Starting with readily available resorcin[n]arene (n = 4, 6) derivatives, we achieved an efficient synthesis of partly hydrogenated belt[n]arene (n = 8, 12) derivatives by means of stitching all fjords through multiple intramolecular alkylation and acylation reactions.8–10 Oxidation of an octahydrobelt[8]arene with excess amounts of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) led to a belt[8]arene-(DDQ)4 adduct, following tandem quadruple aromatization and Diels-Alder reactions. A fully conjugated belt[8]arene derivative was observed in the matrix-assisted laser desorption ionization (MALDI) mass spectrum when the belt[8]arene-(DDQ)4 adduct was subjected to laser irradiation and underwent most probably step-wise retro-Diels-Alder reactions.8 Later, Itami et al.14 and Chi et al.15 independently reported the synthesis of stable and isolable benzannulated analogs of belt[18]arene and belt[12]arene, respectively, using a similar iterative Diels-Alder reaction sequence, followed by reductive aromatization of oxygen-bridged moieties. Figure 1 | Structures of zigzag hydrocarbon belts and heteroatom-embedded analogs. Download figure Download PowerPoint Figure 2 | X-ray crystallographic molecular structure of 3a with the top (left) and side (right) views. Hydrogen atoms and solvent molecules are omitted for clarity. Download figure Download PowerPoint In contrast to the resurgence of interest in zigzag hydrocarbon belts,2–5 construction of heterocycle-containing zigzag molecular belts did not draw attention until recently.16–20 Conceivably, introducing heteroatoms generated a diversity of novel zigzag belt structures. Most importantly, precise inlaying of various heteroatoms or site-selective replacement of the carbon atoms with different heteroatoms would permit fine-tuning of the physical and chemical properties of molecular belts, leading to tailor-made materials useful in the field of supramolecular chemistry and advanced materials. Through repetitive and two-directional condensation reactions between o-arylenediamine derivatives and C-shaped bis(o-benzoquinone)s, Wang and Miao16 synthesized a box-like tetraepoxy nanobelt consisting of tetrazapentacene subunits. Reductive aromatization reactions gave a pyrazine-embedded belt[18]arene derivative, characterized using the MALDI time-of-flight (MALDI-TOF) mass spectrum. Zhu and co-workers19,20 reported the construction of benzo[b][1,4]oxathiine- and benzo[b][1,4]dithiine constituted belt[16]arene derivatives from Ullmann coupling reactions and post-macrocyclization intramolecular electrophilic sulfurization reactions. Wu et al.21 reported very recently the synthesis of nitrogen-doped [(6.)m8]ncyclacenes; the introduction of eight-membered tub-shaped 1,5-diazocine units mitigates substantially the strain of belt[n]arenes which are composed of all six-membered aromatic rings. After successful development of the fjords-stitching strategy in the synthesis of a variety of zigzag hydrocarbon belts, starting from readily available resorcin[n]arenes,8–10 we launched a project to explore the chemistry of heteroatom-embedded zigzag hydrocarbon belts D (Figure 1). Very recently, we17 have shown that the fjords-stitching strategy worked efficiently in the construction of tetraoxa (D, X = Y = Z = O), diazadixoa (D, X = O, Y = Z = NR) and azatrioxa (D, X = Y = O, Z = NR) doped octahydrobelt[8]arene compounds through intramolecular nucleophilic aromatic substitutions and palladium-catalyzed intermolecular C–N bond formations.17 Unfortunately, straightforward transition metal-catalyzed quadruple acridinations of pertriflated resorcin[4]arenes with primary amines did not yield tetraza-linked octahydrobelt[8]arene products (D, X = Y = Z = NAr).17 Also, this type of belt molecules was not delivered by other methods such as intramolecular nitrene insertions to Ar-H bonds and the N-centered radical cyclization reactions of resorcin[4]arene-derived C4-symmetric tetraazides and tetraamines, respectively.22 Aiming at the synthesis of desired N-doped highly strained belt molecules, we exploited multiple Buchwald-Hartwig reactions as means to close all fjords of resorcin[4]arenes.23 Herein, we report the unusual four-fold meta-selective bromination reactions of C4-symmetric 1,3,5,7(1,3)-tetrabenzenacyclooctaphane tetraamides and their efficient conversion to highly strained belt[4]arene[4](1,4-dihydropyridine)s or octahydrobelt[4]arene[4]pyridines. As a useful synthetic platform, the acquired NH-linked belt molecules underwent straightforward N-arylations to produce various functional N-doped zigzag hydrocarbon belts. Oxidation of N-para-methoxyphenyl-substituted belt[4]arene[4](1,4-dihydropyridine) with silver salt furnished a diradical dication belt. Results and Discussion We commenced our study preparing compounds 4, the crucial intermediates for Pd-catalyzed intramolecular C–N bond coupling reactions. Selective meta-brominations of tetramines were not feasible as electrophilic bromination of aniline moiety within macrocycle 1 took place dominantly on the ortho position. On the other hand, under forceful conditions, bromination reactions of 1 failed to afford perbrominated products. These compounds were also anticipated to have the potential to undergo cyclization reactions to form belt structures. To circumvent unfavorable ortho-bromination reactions or non-selective and excessive bromination reactions of 1, we decided to conduct bromination reactions of N-acylated derivatives of 2, assuming that the introduction of an electron-withdrawing N-acyl group would alleviate the reactivity of aromatic ring toward electrophiles. More importantly, if the nitrogen lone pair electrons conjugated with the carbonyl rather than the arene ring, the directing effect of the amino group would probably be overridden by another two alkyl substituents and result in site-selective substitution meta to an amino group. Furthermore, using a sterically bulky acyl group would also aid in driving and directing the position from ortho to meta. Following these guidelines, we acylated compounds 1 with pivaloyl chloride. As illustrated in Scheme 1, in the presence of triethylamine as an acid scavenger, the reaction of 1 with eight equivalents of pivaloyl chloride afforded tetraamide products 2 in excellent yields. Favorably, the AlCl3-promoted bromination reaction of 2 with large excess bromine (16 equiv) in CS2 at ambient temperature indeed led to meta-brominated compounds 3 as the major products in 45% yield. It is important to note that the use of 4 and 8 equiv of bromine resulted in the formation of an inseparable mixture, containing presumably various brominated compounds. Substantiated by the single-crystal X-ray molecular structure of 3a (Figure 2 and Supporting Information Figure S1 and Table S1), a macrocyclic molecule adopting a pinched cone conformation or a boat conformation was observable. Noticeably, most of the pivalamido fragments were not coplanar with their benzene rings, indicating that there was no conjugation between the nitrogen and benzene moieties. Such macrocyclic conformation-governed stereoelectronic effect of pivalamido was most likely responsible for electrophilic bromination at the meta position. The removal of pivaloyl groups was achieved efficiently. Under acidic conditions at 150 °C, tetraamides 3 underwent exhaustive amide hydrolysis to furnish compounds 4 almost quantitatively (Scheme 1). Scheme 1 | Synthesis of 4 from 1 via meta-selective bromination of pivalamidobeneze units. Download figure Download PowerPoint The boat conformation rendered macrocyclic compounds 4 ideal precursors for belt structure through stitching all fjords using intramolecular C–N bond formation. In the presence of 6 equiv of tBuONa and a catalytic amount of Pd2(dba)3 and tBu3P, both 4a and 4b underwent quadruple Buchwald-Hartwig cross-coupling reactions smoothly in refluxing toluene (for 4a) or xylene (for 4b). Gratifyingly, the desired tetraaza-doped zigzag belt molecules, namely, belt[4]arene[4](1,4-dihydropyridine)s or octahydrobelt[4]arene[4]pyridines 5a and 5b were isolated as major products in 63% and 61% yields, respectively (Scheme 2). It is worth addressing that an overall 63% chemical yield of 5a implied a nearly 90% yield for each of the C–N bond-forming reactions. The one-step synthesis of compounds 5 again highlighted the generality and efficiency of the fjords-stitching strategy in constructing zigzag molecular belts from macrocyclic precursors. Scheme 2 | Synthesis of octahydrobelt[4]arene[4]pyridines 5a and 5b. Download figure Download PowerPoint The single-crystal X-ray molecular structure illustrated in Figure 3 and Supporting Information Figure S2 ( Supporting Information Table S2) shows that belt[4]arene[4](1,4-dihydropyridine) 5a adopted a highly symmetric square prism-shaped belt structure. The distances between two distal benzene centroids ranged from 5.68–5.79 Å, while the height was ∼ 2.67–2.79 Å. All six-membered heterocyclic rings were boat-configured, with alkyl substituents being equatorially orientated. The macrocyclic strain forces nitrogen atoms out of the planes of their neighboring benzene rings, and the conjugation of aromatic rings with nitrogen lone-pair electrons were weakened. Consequently, the mean C–N bond length within 5a was 1.43 Å, that is, in between the typical C–N bond length of aromatic amines (1.39 Å) and aliphatic amines (1.47 Å). Figure 3 | X-ray crystallographic molecular structure of 5a with the top (left) and side (right) views. Solvent molecules are omitted for clarity. Distances are given in Å. Download figure Download PowerPoint Belt[4]arene[4](1,4-dihydropyridine)s 5 are versatile building blocks in the fabrication of N-doped zigzag hydrocarbon belts because the secondary amine moieties provide invaluable handles for derivatization. To showcase their synthetic utility and also construct belt molecules of expanded cavities, the synthesis of N-functionalized belt[4]arene[4](1,4-dihydropyridine)s 7 was investigated. A survey of the conditions for the reaction of 5a with bromobenzene 6a indicated that the catalyst or the ligand was crucial for the C–N bond formation. For instance, in the presence of Pd2(dba)3 as a transition metal catalyst and tBuONa as a base, the use of BINAP as a ligand led to the formation of 7a in 38% yield. The chemical yield was improved to 68% when the biphenyl phosphine ligand, XPhos, was used. While 1,3-bis(diphenylphosphino)propane (dppp) appeared detrimental to the reaction from which only a trace amount of 7a was observed, 1,1′-bis(diphenylphosphino)ferrocene (dppf) was beneficial to the catalysis leading to the production of 7a in 89% yield. An excellent yield (94%) of 7a was achieved when 4-(di-tert-butylphosphaneyl)-N,N-dimethylaniline24 was employed as a ligand. Under the optimized catalytic conditions, the reaction of both 5a and 5b with various arylbromides 6 (12 equiv) proceeded efficiently to afford the corresponding N-aryl-substituted belt[4]arene[4](1,4-dihydropyridine)s 7 (Scheme 3). For example, N-arylated belt products bearing either an electron-donating or electron-withdrawing group on the para position of the benzene ring were obtained with yields ranging from 55% to 77%. Meta- and ortho-methoxylated arylbromides reacted equally well to produce belts 7d and 7e in 99% and 77%, respectively. Sterically bulky 2,4-dimethoxyphenyl and 2,4,6-trimethoxyphenyl groups were also readily installed on the rim of the belt[4]arene[4](1,4-dihydropyridine) to give products 7f and 7g (Scheme 3). Scheme 3 | Synthesis of functional belt[4]arene[4](1,4-dihydropyridine)s 7 from fourfold N-arylation reactions of 5. Download figure Download PowerPoint The structures of products 7 were supported by their spectroscopic data. The observation of single sets of 1H and 13C NMR spectra indicated the symmetric structures of all N-arylated belts in solution. In the solid-state, highly C4-symmetric structures were also determined unambiguously, employing single-crystal X-ray diffraction analysis. Molecular structures of 7a, 7c, and 7h in Figure 4 and Supporting Information Figures S3–S7 ( Supporting Information Tables S3–S7) showed convincingly that the installation of aryl groups on the nitrogen atoms around the rim increased the cavity substantially. In the case of 7a, for instance, the distance between the distal phenyls at the open rim and between the far end carbon of the N-phenyl and the plane, defined by lower rim carbons, were 11.07 and 6.36 Å, respectively. Scrutiny of all C–N bond lengths also revealed that each N-aryl substituent formed conjugation with the nitrogen inlayed in the skeleton of the belt structure. In the case of 7f and 7g, however, each plane of N-2,4-dimethoxyphenyl and N-2,4,6-trimethoxyphenyl rings was nearly in the bisector plane of each boat-configured 1,4-dihydropyridine ring. Such conformation could prevent steric repulsion between the proximal N-2,4-dimethoxyphenyl substituents in 7f and N-2,4,6-trimethoxyphenyl substituents in 7g. The steric interaction between bulky N-2,4,6-trimethoxyphenyl substituents or between methoxy groups on the ortho positions of the phenyls even caused distinct deformation of the square prism-shaped belt structure of 7g. Consequently, the lone-pair electrons of the inlaid nitrogen atom were unable to conjugate with the aryl group on the rim. Figure 4 | X-ray crystallographic molecular structure of 7a (a), 7c (b), 7f (c), and 7g (d) with top (top) and side (bottom) views. Solvent molecules are omitted for clarity. Distances are given in Å. Download figure Download PowerPoint We then attempted the oxidation of the N-doped hydrocarbon belts. While oxidative aromatization of 5 with DDQ resulted in an insoluble mixture, we found that electrooxidation of belt compounds substituted with a p-methoxy group such as 7c, 7e, and 7f led to the development of blue, purple, and red color of their dichloromethane (DCM) solutions, respectively ( Supporting Information Figure S9). They also underwent oxidation rapidly with Ag[Al(OtBuF)4] to form colorful solutions. Gratifyingly, the oxidation product of 8 precipitated as single crystals in 60% yield (Scheme 4). Compound 8 was stable under atmospheric conditions. X-ray diffraction experiment, electron paramagnetic resonance (EPR), and superconducting quantum interference device (SQUID) measurements indicated that product 8 was a diradical dication salt ( 7c++.)2[Al(OtBuF)4]−. As illustrated in Figure 5 and Supporting Information Figure S8 ( Supporting Information Table S8), the bond lengths of a pair of distal CPMP-N+. (1.350 Å) and C–O (1.325–1.329 Å) bonds were markedly shorter than that of other pairs of CPMP-N (1.410–1.425 Å) and C–O (1.365–1.373 Å) bonds. In the solid-state, two diradical dication belts were head-to-tail arrayed; in between, there were two anions [Al(OtBuF)4]− ( Supporting Information Figure S8): One of the bulky anions was accommodated nicely by the cavity formed by four p-methoxyphenyl (PMP) segments (Figure 5). Zero-field splitting, accompanied by the forbidden Δms = ±2, was shown by EPR spectroscopy ( Supporting Information Figure S10), and antiferromagnetic intra- and intermolecular interaction revealed by SQUID measurement ( Supporting Information Figure S11) indicated that compound 8 was a singlet diradical dication species. The average spin–spin distance was calculated as 8.65 Å, close to the distance between two distal PMP carbons attached to single-electron-oxidized nitrogen atoms (Figure 5). Scheme 4 | Formation of diradical dication salt 8 from oxidation of 7c. Download figure Download PowerPoint Conclusion We have developed an efficient fjords-stitching method to construct a highly strained belt[4]arene[4](1,4-dihydropyridine)s from readily available macrocyclic reactants. The synthesis featured abnormal meta-bromination of each pivalamidobeneze subunits of C4-symmetric calixarenes and four-fold palladium-catalyzed intramolecular C–N bond coupling reactions. We have also demonstrated that the acquired belt[4]arene[4](1,4-dihydropyridine)s provided an invaluable springboard for the convenient fabrication of novel zigzag molecular belts with varied cavity structures and desired functions. Further applications of the products are being actively pursued in our laboratory, and the results will be reported in due course. Figure 5 | X-ray crystallographic molecular structure of 8 with the top (left) and side (right) views. For clarity, two anions and a solvent molecule are omitted for the top view, while the side view shows one included anion. Distances are given in Å. Download figure Download PowerPoint Supporting Information Supporting Information is available and includes all experimental details and copies of 1H-, 13C-NMR, and EPR spectra of products. X-ray crystallographic data were submitted as Crystallographic Information Files (CIFs) to the Cambridge Crystallographic Data Centre (CCDC). Conflict of Interest The authors declare no competing interests. Acknowledgments We thank the National Natural Science Foundation of China (grant nos. 22050005, 21732004, and 21821001) and the Tsinghua University Initiative Scientific Research Program (grant no. 2019Z07L01004) for generous financial support.
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