Synthesis of covalent organic pillars as molecular nanotubes with precise length, diameter and chirality

Nanotubes with confined one-dimensional interiors enable applications in molecular recognition and storage, catalysis, selective transport across membranes, and nano-electronics/mechanics. While carbon nanotubes and numerous polymeric tubular assemblies are known, their structural heterogeneity limits precise control and integration into complex systems. Achieving atomically precise, discrete molecular nanotubes of uniform length, diameter, and single handedness is essential to exploit anisotropic nanochannels. The authors target a single-molecule nanotube constructed by stacking macrocyclic units covalently, addressing the scarcity of length/diameter >1 nanotubes. They aim to synthesize a chiral, well-defined covalent organic pillar (COP-1) via imine condensation of rim-differentiated penta-aldehyde macrocycles with p-phenylenediamine linkers, and to probe host-guest recognition in its 1D channel with α,ω-disubstituted n-alkyl chains to elucidate size/electronic complementarity and length dependence.

Prior work has established diverse nanotubular systems, including carbon nanotubes and soft-matter or polymeric nanotubes, with uses in catalysis, transport, and molecular devices (refs 1–20). However, many assemblies lack structural precision. Advances in discrete macrocycles and carbon nanobelts (refs 24–26) have expanded building blocks, yet single-molecule nanotubes with high aspect ratios remain rare (refs 21–23). Stacking concave macrocycles such as cyclodextrins, cyclotriveratrylenes, resorcinarenes, and calixarenes has yielded cavitands and tubular capsules (refs 27–38). Pillar[n]arenes and rim-differentiated variants (refs 39–44) provide shape-persistent platforms, and noncovalent nanotube assemblies, including length-controlled and chiral systems, have been shown (refs 45–47, 59). Porous organic cages and covalent organic frameworks demonstrate discrete porous architectures and dynamic covalent strategies relevant to precision assembly (refs 49–55). This work builds on these developments by using reversible imine chemistry to covalently link macrocycles into a discrete, chiral molecular nanotube with precise dimensions.

Synthesis: COP-1 was synthesized by [2+5] imine condensation between rim-differentiated p-formyl-tiara[5]arene macrocycles (p-formyl-T[5], 20 mg, 0.027 mmol) and p-phenylenediamine (7.30 mg, 0.068 mmol) in CHCl3 (3 ml) under reflux for 8 h, affording COP-1 in quantitative NMR yield and 94% isolated yield after workup (EtOAc and MeOH washes, vacuum drying at 90 °C). Chiral resolution: The racemate was separated by HPLC on a Daicel CHIRALPAK IE column (5 µm, 10 mm ID × 250 mm), mobile phase CHCl3/MeOH = 7:3, 2.0 ml min−1, detection at 300 nm, yielding enantiopure (M)-COP-1 and (P)-COP-1. ECD spectra showed mirror-image signals; the first fraction with a positive Cotton effect at ~385 nm crystallized and was assigned as (M)-COP-1. Crystallography: Single crystals were grown by slow vapour diffusion/evaporation from CH2Cl2/MeOH or CH2Cl2/CHCl3. Data were collected on XtaLAB Synergy instruments (Cu Kα, λ = 1.54184 Å), processed with CrysAlisPro, solved with ShelXT and refined with ShelXL/Olex2. COP-1 crystallized in P212121 (orthorhombic); inclusion complexes [Br(CH2)10Br⊂COP-1], [HO(CH2)12OH⊂COP-1], and [Br(CH2)9Br⊂COP-1] were also solved (P212121). Channel volume was calculated with VOIDOO using a 1.4 Å probe. Spectroscopy and mass spectrometry: 1H NMR (400 MHz) in CDCl3 at 298 K, including COSY, DOSY, and titrations, probed host-guest interactions; HRMS identified inclusion complexes. ECD characterized chirality. Host-guest studies: A panel of α,ω-dibromoalkanes, α,ω-alkanediols, and mono-substituted 1-bromoalkanes/1-alkanols were screened. Criteria for inclusion were the appearance of highly shielded guest resonances (<0 ppm) and DOSY co-diffusion with COP-1. Thermodynamics: Isothermal titration calorimetry (Affinity ITC) in CHCl3 at 298 K provided Ka values and thermodynamic parameters for guests at and near critical lengths; blanks in CHCl3 were subtracted; data were fit with NanoAnalyze. For systems with no measurable heat, 1H NMR titrations in CDCl3 were fit using BindFit. Computation: DFT (Gaussian 16) B3LYP-D3/6-31G(d) optimized structures and generated electrostatic potential maps, revealing an electron-rich channel surface with electron-deficient edges.

Structure: COP-1 is a discrete, chiral single-molecule nanotube formed by [2+5] imine condensation of two penta-aldehyde macrocycles with five p-phenylenediamine linkers, yielding a hollow twisted pentagonal prism. It possesses a 1D channel of length ~2.0 nm (tip-to-tip), inner diameter ~4.7 Å, and estimated void volume ~440 Å3. A racemic mixture was resolved into (M) and (P) enantiomers showing mirror-image ECD; (M)-COP-1 crystallized in P212121. Channel properties: The electrostatic potential map shows a mostly electron-rich interior, with electron-deficient regions at the rim edges. Host-guest selectivity: Strong binding is highly length-dependent and requires electron-withdrawing or polar termini. Critical lengths: α,ω-dibromoalkanes bind strongly for n ≥ 10 methylenes; α,ω-alkanediols require n ≥ 12. Mono-functional guests also bind when sufficiently long (1-bromoalkanes n ≥ 12; 1-alkanols n ≥ 13). Nonpolar n-alkanes showed no strong interaction. NMR signatures: Encapsulated guests display highly shielded 1H signals below 0 ppm and share DOSY diffusion coefficients (~10−7 cm2 s−1) with COP-1, confirming inclusion. Binding constants (CHCl3 unless noted): 1,11-dibromoundecane Ka = (1.42 ± 0.27) × 10^6 M−1; 1,10-dibromodecane Ka = (1.19 ± 0.06) × 10^5 M−1; 1,9-dibromononane Ka = (2.41 ± 0.19) × 10^3 M−1; 1,8-dibromooctane Ka = (2.40 ± 0.10) × 10^3 M−1 (by 1H NMR titration in CDCl3). 1,13-tridecanediol Ka = (3.04 ± 0.02) × 10^5 M−1; 1,12-dodecanediol Ka = (2.36 ± 0.13) × 10^5 M−1; 1,11-undecanediol Ka = (3.45 ± 0.23) × 10^4 M−1; 1,10-decanediol Ka = (9.43 ± 0.22) × 10^2 M−1. Ka values span ~10^3–10^6 M−1 (dibromides) and ~10^2–10^5 M−1 (diols). These are ≥3 orders of magnitude larger than for per-methylated pillar[5]arene with the same guests. Thermodynamics: Guests shorter than the critical length have comparable enthalpic gains but more negative entropic contributions, reducing overall affinity, consistent with configurational/conformational penalties in mismatched complexes. For the shortest guests (e.g., 1,8-dibromooctane; 1,10-decanediol), ITC showed no measurable heat; NMR titration still revealed modest binding. Solid-state inclusion: X-ray structures of [Br(CH2)10Br⊂(M)-COP-1] and [HO(CH2)12OH⊂(M)-COP-1] show fully extended anti-periplanar guest conformations with terminal groups seated at electron-deficient rim edges. The shorter [Br(CH2)9Br⊂(P)-COP-1] reveals the distal Br adopting an energetically unfavorable gauche conformation stabilized by a C–Br⋯π interaction (3.62 Å) with an aromatic ring, demonstrating guest contortion under confinement.

The study demonstrates that a structurally precise, chiral covalent molecular nanotube can be accessed through dynamic covalent assembly of rim-differentiated macrocycles, delivering a rigid, pre-organized host with a uniform 1D channel. The strong, sharply length-dependent binding of α,ω-disubstituted n-alkyl chains highlights the critical role of size and electronic complementarity in selective molecular recognition within confined spaces. The substantially higher Ka values relative to a single pillar[5]arene macrocycle are attributed to preorganization, extended inner surface contacts, and the rigid, inversion-resistant conformation, which reduces entropy loss upon binding. Conversely, diminished affinities for guests below the critical length arise from greater entropic penalties and inability to simultaneously engage both electron-deficient rim regions. The solid-state observation of a gauche distortion in a mismatched guest, compensated by C–Br⋯π interaction, provides rare crystallographic evidence of confinement-induced conformational adaptation, offering insights into how nanoconfinement modulates guest geometry and energetics.

A pair of enantiomeric, discrete covalent organic pillars (COP-1) were synthesized efficiently via reversible imine bond formation between rim-differentiated tiara[5]arene macrocycles and p-phenylenediamine linkers, yielding a 2-nm-long, 4.7-Å-wide nanotube with ~440 Å3 interior volume. The chiral nanotubes exhibit pronounced, length- and end-group-dependent recognition of α,ω-disubstituted n-alkanes, with high affinities for guests at or above critical lengths and weaker binding below. The pre-organized, rigid architecture underlies enhanced binding strengths and selectivity, while X-ray structures reveal confinement-driven guest conformational changes. The modular strategy is applicable to paracyclophane and pillar[n]arene derivatives and could be extended to diverse nanorings and nanobelts, accelerating the synthesis of discrete molecular nanotubes and potentially pure carbon nanotubes of tailored sizes and functions. Future work can leverage these precise channels to probe reactivity and transport under nanoconfinement and enable applications in catalysis, biointerfaces, and molecular nanotechnologies.

The host shows no strong interactions with non-polar n-alkanes, limiting binding to guests with electron-withdrawing or polar termini and appropriate lengths. For shorter guests, ITC detected no measurable heat in some cases, and binding is substantially weaker, indicating a narrow optimal size range for high-affinity recognition and potential sensitivity to solvent and guest functionalization.