Open AccessCCS ChemistryRESEARCH ARTICLE7 Dec 2022Synthesis of Finite Molecular Nanotubes by Connecting Axially Functionalized Macrocycles Liang-Liang Mao, Hongyan Xiao, Jin-Qin Zhao, Zhuo Diao, Wen Zhou, Hongwei Li, Chen-Ho Tung, Li-Zhu Wu and Huan Cong Liang-Liang Mao Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 Google Scholar More articles by this author , Hongyan Xiao Key Laboratory of Bio-Inspired Materials and Interfacial Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 Google Scholar More articles by this author , Jin-Qin Zhao Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author , Zhuo Diao Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author , Wen Zhou Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871 Google Scholar More articles by this author , Hongwei Li Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871 Google Scholar More articles by this author , Chen-Ho Tung Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author , Li-Zhu Wu Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author and Huan Cong *Corresponding author: E-mail Address: [email protected] Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190 School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202101728 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Monodispersed molecular nanotubes, particularly those with uniform lengths, are challenging targets for chemical synthesis. Here, we report the general design and efficient synthesis of finite molecular nanotubes, utilizing a dynamic assembly strategy to precisely stack axially functionalized macrocycles by chemical connections. Discrete tubular molecules, ranging from 7.8 to 19.8 kDa with covalent or coordinative connections, have been prepared from modular macrocyclic building blocks through highly convergent routes. The discrete molecular nature and structural anisotropy of these synthetic tubes warrant postsynthesis modifications and solution processing methods, as demonstrated by the controllable orientations when deposited onto different prefabricated surfaces. Download figure Download PowerPoint Introduction The assembly of craftily designed molecular building blocks can facilitate efficient construction of organized chemical structures. For instance, (metallo)organic cages and frameworks based on dynamic covalent or coordinative assembly have been developed with significant success in the context of zero-, two-, and three-dimensional architectures.1–8 Nonetheless, the corresponding one-dimensional molecular tubes are underdeveloped to date, much less the tubes with controllable lengths.9–17 One-dimensional hollow nanostructures feature confined tubular space and anisotropic properties, representing a recently emerging category of artificial materials with increasing functions and applications.18–30 With a number of noteworthy exceptions,9–17,31–37 (metallo)organic nanotubes are mostly obtained through self-assembly via noncovalent interactions such as hydrogen bonds or π–π interactions.38–55 As a consequence, the monodispersity and stability of molecular nanotubes remain difficult to control. Here, we report the structural design and bottom-up synthesis of finite molecular nanotubes as discrete and isolable molecules featuring dynamic covalent or coordinative assembly56–59 of axially functionalized macrocycles. These macrocyclic modules contain positions for orthogonal functionalization for chemical connections, and their stepwise oligomerizations are precisely manipulated to achieve uniform nanotube lengths. As a proof of concept, monodispersed tubular molecules were efficiently synthesized with high yields as trimers or pentamers, which further showcased controllable orientations when deposited onto different prefabricated surfaces. Experimental Methods All reactions were carried out using flame-dried glassware under nitrogen atmosphere unless otherwise noted. Commercially available reagents were used as received. 1H, 13C, and 31P NMR spectra were recorded with a Bruker Avance 400 spectrometer (Bruker, Germany) and are internally referenced to residual protio solvent signals. Diffusion-ordered NMR spectroscopy (DOSY) experiments were recorded with a Bruker Avance 600 spectrometer (Bruker, Germany). Infrared spectra were recorded on a Varian 3100 Fourier transform infrared spectrometer (Varian, United States). Mass spectrometry experiments were performed with a Bruker SolariX XR Fourier transform ion cyclotron resonance mass spectrometer (Bruker, United States) [for high-resolution electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI)] or an AB Sciex MALDI-time-of-flight (TOF)/TOF 5800 mass spectrometer (AB Sciex, United States) (for MALDI). Atomic force microscopy (AFM) measurements were conducted on a SPID Bruker FastScan AFM (Bruker, United States) under the noncontact mode in air. Further experimental details are available in the Supporting Information. Results and Discussion Molecular design At the outset, the macrocyclic core structure, fluorenylidene-aza[16]cyclophane (FLAC, Figure 1a), was employed as a modular unit for the target tubular molecules with the following considerations: (1) the C3-symmetry and rigidity of the macrocyclic scaffold are beneficial for facile global functionalizations and robust multiple-site assembly60–64; (2) versatile side-chains can be extended in the radial directions from the three nitrogen atoms embedded in each macrocycle backbone, allowing chemical modifications for tunable solubility and hydrophobicity65; and (3) each fluorenylidene moiety is implemented with two aryl bromides for axial functionalizations. Indeed, the crystal structure of the FLAC core (Figures 1b and 1c and Supporting Information Figure S71) shows that the three dibromo-fluorenylidene subunits are almost perpendicular to the macrocyclic plane, and the carbon–bromine bonds are positioned toward the axial directions. These structural arrangements facilitate the installation of connectable moieties for nanotube constructions. Figure 1 | The design of building blocks and finite molecular nanotubes. (a) The axially functionalized macrocycle FLAC as building block. (b) Side- and (c) top-view of the crystal structure of the C3-symmetrical FLAC core (side-chains and H atoms were omitted for clarity). (d) Covalent- and (e) coordinative-connected finite molecular nanotubes: computationally optimized geometry of FLAC trimers (substitutions on N and P atoms were simplified as methyl groups during calculations; H atoms were omitted for clarity). Download figure Download PowerPoint Employing the axially functionalized FLAC derivatives, we speculated that the reversible connections, either through covalent imine bonds or coordinative platinum(II)-pyridine bonds, could enable error-correction mechanisms to promote the formation of organized tubular structures during multiple-site assembly.66–70 Moreover, the lengths of the finite nanotubes are defined by the degree of oligomerization that can be manipulated by the stoichiometry of the FLAC-derived modules. Hence, the imine- and platinum-containing FLAC trimers were chosen as the initial targets, both of which show triple helix structures according to density functional theory calculations (Figures 1d and 1e). Synthesis and characterizations The synthesis commenced with the FLAC-derived functionalized modules (Figure 2). Starting from the commercially available diarylamine 1, bromine-substituted macrocycles 2a and 2b were obtained in three steps ( Supporting Information Figure S1).71 Two types of hydrophobic side-chains were installed onto the nitrogen atoms of 2a and 2b, respectively. Such modifications in the radial direction would differentiate these FLAC-derived building blocks after assembly, as well as enhance the solubility of the finite molecular nanotubes. Next, these two molecules served as linchpin compounds for axial functionalizations through versatile coupling reactions. Direct Suzuki–Miyaura couplings with aryl borates provided the C3-symmetrical precursor molecules, aldehyde 4 and aniline 5a/ 5b, respectively, for covalent assembly. In parallel, Sonogashira coupling with silylacetylene followed by desilylation extended the axial directions, and afforded terminal alkyne-functionalized FLAC 3a and 3b, which could be converted to pyridine 6 and alkynyl-platinum 7 for coordinative assembly. Figure 2 | Preparation of FLAC-derived building blocks. Download figure Download PowerPoint With the modular macrocyclic building blocks in hand, imine condensation between 5a and excess aldehyde 4 under acidic conditions afforded the desired trimer nanotube 8 bearing aldehyde terminal groups (Figure 3a).72–75 Similarly, platinum-containing trimer nanotube 9, with pyridine terminal groups, was obtained from 7 and excess pyridine 6 in the presence of silver nitrate (Figure 3b).76–78 Both assembly processes were highly efficient and chromatography-free with almost quantitative yields. With molecular weights of 7.8 kDa (for 8) and 11.4 kDa (for 9), the trimer molecular nanotubes were characterized by NMR with well-resolved peaks showing C3-symmetrical connections at six positions within each molecule. The 1H NMR spectrum of 8 ( Supporting Information Figure S33) shows the terminal aldehydes as a singlet at 10.06 ppm and the formation of imines as a new characteristic singlet at 8.56 ppm. The peripheral side chains display marginal shifts compared with the precursors 4 and 5a. The integrations of the peaks of aldehydes and side chains indicate a 2:1 ratio of the corresponding building blocks. The nanotube 9 exhibits broad proton NMR signals ( Supporting Information Figure S41) likely due to slow tumbling motions on the NMR timescale, with the terminal pyridyl moieties distinctly downshifted from other aromatic peaks. High-resolution mass spectra showed matching isotopic distributions with the simulated patterns ( Supporting Information Figures S38 and S46). The above evidence indicates that the trimer nanotubes have been successfully prepared. Figure 3 | Synthesis and DOSY characterization of imine- and Pt-containing finite molecular nanotubes. Download figure Download PowerPoint Encouraged by the efficient preparation of trimers, we next aimed at pentamer nanotubes through stepwise oligomerization79–84 of FLAC-derived building blocks (Figures 3c and 3d). Like the trimers, the terminal groups should be aldehyde and pyridine for the imine- and Pt-containing finite nanotubes, respectively, due to easier purification and higher stability. Accordingly, the initial stoichiometry ratios of the first assembly steps for both pentamers should be reversed, with excess aniline 5b (replacing 5a because of better solubility) and alkynyl-platinum 7, respectively. The resulting trimer intermediates were precipitated and directly used in the second assembly steps in the presence of excess complementary modules, thereby affording the pentamer nanotubes (14.6 kDa for 10 and 19.8 kDa for 11) with excellent efficiency over two steps. In analogy to the trimers, the 1H NMR spectra of both pentamer nanotubes indicate a 3:2 ratio of the corresponding building blocks based on the peak integrations of terminal groups and side chains ( Supporting Information Figures S49 and S53). With estimated lengths of 5.6, 6.1, 9.4, and 10.1 nm for 8– 11, respectively, DOSY85 was performed to characterize these four finite nanotubes, and the size parameters derived from the DOSY data are consistent with the desired structures as discrete and monodisperse molecules ( Supporting Information Table S1). In addition, all four molecular nanotubes remain stable when stored under ambient conditions for at least one month. Orientation control on prefabricated surfaces These novel finite molecular nanotubes exhibit monodispersity, stability, solubility, as well as structural anisotropy bearing hydrophobic side-chains and polar terminal groups. The combination of these attractive features should allow postsynthesis modifications and solution processing methods, which are uncommon for noncovalently assembled nanotubes. Accordingly, we reasoned that due to the abundance of alkyl chains on the sidewalls, the molecular nanotubes 8– 11 should prefer recumbent positions when deposited onto a hydrophobic surface. In contrast, those with upright positions would be observed on chemically modified surfaces86 that can strongly interact with the terminal groups ( Supporting Information Figure S60). AFM analyses showed that isolated particles were predominant for drop-cast samples of 8– 11 on freshly cleaved mica surfaces ( Supporting Information Figures S61–S64). The observed particle height data accord well with the single layer of finite molecular nanotubes adopting the recumbent positions. To effect the upright positions, we next modified mica substrates by chemically grafting functional groups: the primary amine-fabricated mica surface underwent condensation with the aldehyde terminal groups of trimer 8 and pentamer 10 (Figures 4a and 4b and Supporting Information Figures S65 and S67); and in parallel, the sulfonic acid-fabricated mica surface was able to bind the basic pyridyl terminal groups of trimer 9 and pentamer 11 (Figures 4c and 4d and Supporting Information Figures S66 and S68). Indeed, the AFM images of the resulting samples displayed widespread dots with the measured height data matching the nanotube structures at the upright positions. These results showcase that the orientations of finite molecular nanotubes can be controlled by chemical manipulations when deposited onto prefunctionalized solid surfaces. Figure 4 | Schematic and AFM images of upright orientations of finite molecular nanotubes deposited onto prefabricated surfaces. Upright positions of 8 (a) and 10 (b) on the primary amine-fabricated mica substrate. Upright positions of 9 (c) and 11 (d) on the sulfonic acid-fabricated mica substrate. Download figure Download PowerPoint Conclusion We have established new designs and productive synthesis of discrete one-dimensional finite molecular nanotubes with atomically precise structures. By providing straightforward access to the monodispersed trimer and pentamer nanotubes through dynamic covalent or coordinative assembly, our approaches are amenable to chemical modifications with profound potential for length control and versatile functionalizations. In addition, the soluble, molecular nature of the finite nanotubes makes solution processing methods viable. As a demonstration, the anisotropic molecular nanotubes can be deposited onto predesigned surfaces with predominantly recumbent or upright positions in a predictable and controllable fashion. With this proof-of-concept report on the highly efficient one-dimensional assembly of the FLAC scaffold, we aim to highlight that the lengths of the molecular nanotubes can be precisely controlled via synthetic chemistry approaches. We speculate that discrete molecular nanotubes with various lengths and diameters are feasible by employing modular macrocyclic building blocks. Further development and applications of these emerging one-dimensional hollow nanostructures are ongoing in our laboratory and will be reported in due course. Supporting Information Supporting Information is available includes the synthetic procedures, compound characterizations (including NMR, IR, mass spectroscopy, UV–vis absorption, and DOSY spectra, Figures S2–S58, S69, and S70), calculations based on DOSY data (Table S1 and Figure S59), AFM analyses (Figures S61–S68), X-ray crystallography (Figure S71 and Tables S2 and S3), and theoretical calculations (Figures S72 and S73 and Tables S4 and S5). Conflict of Interest H.C., L.-L.M., L.-Z.W., and C.-H.T. have filed a patent application based on this work. Funding Information Financial support was provided by the National Natural Science Foundation of China (nos. 21922113, 22088102, 21672227, 21988102, and 22071257), the Chinese Academy of Sciences (no. XDB17000000), the National Key Research and Development Program of China (no. 2017YFA0206903), K. C. Wong Education Foundation, and TIPC Director’s Fund. Acknowledgements The authors thank Profs. Congyang Wang, Junfeng Xiang, Jie Cui, Qian Li (ICCAS), Run Shi, and Ye Tian (TIPC-CAS) for compound characterizations and helpful discussions. The authors also thank the NMR facility of the National Center for Protein Sciences at Peking University.