Thermodynamic Locking of Conformational Chirality in a [9]Cycloparaphenylene

Abstract

Herein, we report the thermodynamic locking of conformational chirality in a [9]­cycloparaphenylene (CPP) by external appending of (R)- or (S)-BINOL units. Through-space steric interactions induce asymmetric torsion in the CPP backbone, generating a strained nanohoop with the lowest-energy conformer (ΔG = −2.9 kcal mol^–1, corresponding to >99% population of the preferred conformer at 293 K). Temperature- and solvent-dependent circular dichroism (CD) spectra exhibit minimal signal variation, in marked contrast to conventional dynamic chiral systems and the monomeric precursor. Variable-temperature NMR reveals rapid interconversion (ΔG ^‡ = 12.4 kcal mol^–1), confirming fast kinetics that enable equilibration to the thermodynamically favored twisted conformation. Single-crystal X-ray diffraction and time-dependent density-functional theory (TD-DFT) calculations, including model compounds devoid of BINOL chromophores, unambiguously assign the intense Cotton effects to torsionally distorted CPP-centered π–π* transitions.

Introduction

Dynamic conformational chirality describes molecular systems in which the chiral element interconverts on the experimental time scale, − as exemplified by configurationally labile biaryls, tertiary amines, carbanions, , and [4],[5]-helicenes (Figure a). , This concept has found broad application in asymmetric catalysis , and supramolecular chiral assemblies. − Recently, it has emerged as a powerful strategy for designing chiral materials, − enabling modulation of chiroptical properties without requiring expensive chiral catalysts or laborious resolution procedures. This approach exploits external chiral auxiliaries to introduce a thermodynamic bias among transient diastereomers, thereby inducing and amplifying chiral asymmetry in otherwise dynamically racemic systems (Figure ). Despite these advances, dynamically chiral materials remain at an early stage of development and are currently limited by two major challenges. First, they often exhibit pronounced sensitivity to temperature and solvent variations, which can erode the population of the induced lowest-energy conformer and diminish the overall chiroptical response. Second, their structural diversity is severely restricted as most systems rely on helicene-based scaffolds. This narrow structural scope limits the accessible range of chiroptical properties, thermal racemization barriers, and compatibility with diverse functional environments. ,− ,,−

1.

(a) Representative examples of dynamic chirality; demonstration of enantiomerization barrier. ,,,,,, (b) Representative examples of dynamic chirality in small molecules reported by Katoono, Mori, Melle-Franco and Mateo-Alonso, Nuckolls and Jin, Naubron and Pieters, and Tilley. (c) Our strategy for synthesizing chiral [9]­CPP by dynamic chirality (The dotted curved arrows indicate that the chiral nanohoop is twisted by BINOL groups.).

To address these challenges, this study introduces a platform that integrates rigid macrocycle with dynamic chirality in [n]­cycloparaphenylenes (CPPs). This approach not only expands dynamic chirality beyond traditional helicene scaffolds but also leverages the inherent rigidity of the nanohoops to stabilize induced conformational asymmetry (Figure c). In contrast to prior chiral CPPs, which rely on covalent incorporation of scarce chiral units directly into the hoop, − we append (R)- or (S)-BINOL units externally to induce asymmetric ring torsion of adjacent atropisomeric biphenyl units. Critically, the rigid macrocyclic framework imparts strong thermodynamic stabilization to the dynamic chiral system. Single-crystal X-ray analysis confirms a twisted conformation. Together with time-dependent density-functional theory (TD-DFT) calculation, the intense Cotton effect at 360–550 nm is assigned to CPP-centered π–π transitions* modulated by ring torsion. Temperature- and solvent-dependent circular dichroism (CD) spectra reveal negligible changes in signal intensity and shape, demonstrating robust thermodynamic conformational locking and markedly enhanced stability relative to conventional dynamic chiral systems. ,,,,

Variable-temperature NMR (VT-NMR) experiments further indicate rapid atropisomeric isomerization, with a low energy barrier of ΔG ^‡ = 12.4 kcal mol^–1. Collectively, these findings establish a new class of strain-induced, configurationally dynamic yet thermodynamically biased chiral nanohoops that combine the rigidity with strong, persistent chiroptical responses, paving the way for advanced nanomaterials.

Results and Discussion

Synthesis and Characterization

The syntheses of (R/S)-1 are outlined in Scheme . The key chiral intermediates (R)-2 and (S)- 2 were obtained in 92% yield via nucleophilic aromatic substitution of 4,7-dibromo-5,6-difluorobenzo­[c]­[1,2,5]­thiadiazole with (R)- or (S)-BINOL under basic conditions (K₂CO₃, dimethylformamide (DMF), room temperature (rt)). Suzuki–Miyaura coupling of (R/S)-2 with 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane afforded (R/S)-3 in an 86% yield. Subsequent borylation with B₂Pin₂ in 1,4-dioxane gave the corresponding bis­(boronate) ester (R/S)-4 in 67% yield. Cyclization to the target (R/S)-1 was achieved using the gold-mediated method developed by Osakada and co-workers. , The structure of chiral (R)- 1 was unambiguously confirmed by single-crystal X-ray diffraction. Both enantiomers ((R)-1 and (S)-1) were further characterized by ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (Supporting Information).

1. Synthesis of Chiral CPPs .

^a Reagents and conditions: (I) K₂CO₃, DMF, overnight, rt, 92%. (II) PdCl₂(Dppf), K₂CO₃, toluene/ethanol/H₂O = 4:1:1, overnight, 90 °C, 86%. (III) B₂Pin₂, Pd­(OAc)₂, S-Phos, KOAc, 1,4-dioxane, overnight, 90 °C, 67%. (IV) [Au₂Cl₂(dcpm)], Cs₂CO₃, toluene/ethanol/H₂O = 4:1:1, 24 h, 50 °C. (V) PhICl₂, DMF, overnight, rt [(two steps; IV, V) 64%].

Thermodynamic Conformational Locking of Dynamic Chirality

The successful and robust chiral induction was validated by circular dichroism (CD) spectroscopy (Figure ). Compounds (R/S)-3 and (R/S)-1 display intense, mirror-symmetric Cotton effects in the 355–420 and 360–550 nm regions, respectively (highlighted in pink, Figure c,d). Temperature-dependent chiroptical responses are a hallmark of conventional dynamic chirality systems, as evidenced by prior reports and the monomeric precursor (S)-3 in this work (Figures f, S9, and S12). ,, In marked contrast, the CD signal of (S)-1 in the 360–550 nm region exhibits only minimal attenuation upon heating (Figure e, blue trace; Figures g and S11), indicative of negligible conformational perturbation. Specifically, cooling from 333 to 293 K induces only slight intensity changes, far less pronounced than in monomer (S)-3 (Figures e–g, S7–S9, S11, and S12). Further cooling to 273 K yields no observable spectral variation. This phenomenon suggests the stabilization of dynamic chirality in the systems at 293 K. Importantly, full signal recovery occurs upon returning to 298 or 263 K (Figure S10), confirming that these minor temperature-induced changes arise from reversible dynamic equilibration rather than irreversible racemization. The enhanced robustness of (S)-1 likely stems from the rigid macrocyclic framework, which effectively stabilizes the induced conformation in dynamically chiral systems. To simplify the otherwise complicated conformations, the subtle conformational transition was treated as a two-state equilibrium, van’t Hoff analysis of the temperature-dependent CD intensities afforded the thermodynamic parameters ΔG (293.15 K) = −2.92 kcal mol^–1, ΔH = −6.89 kcal mol^–1, and ΔS = −13.6 cal mol^–1 K^–1 (Figures h and S13). Furthermore, the CD signal of the (R/S)-1 remains small changed across solvents compared with the published result ,,, (Figures S18 and S20). These results establish that the observed chiroptical response originates from the dynamically atropisomeric chiral macrocycle and exhibits stability toward temperature and solvent perturbations. This work thus demonstrates, for the first time, effective thermodynamic conformational locking in a dynamic chirality platform through the incorporation of a rigid cycloparaphenylene scaffold. These chiroptical signatures originate from the BINOL-induced twisted terphenyl moiety and distorted CPP skeleton, as corroborated by time-dependent DFT (TD-DFT) calculations (Figures S14, S15, S60–S66, and ). To validate the chiral structure of distorted CPP skeleton and chiroptical behavior, we further investigated the circularly polarized luminescence (CPL) properties of this class of chiral [9]­CPPs (Figure S4), with a quantum yield (QY) of 36.13% for (R/S)-1. The CPL spectra of (R/S)-1 exhibited maxima at 559 nm upon excitation at 340 nm (Figure S4). The g _lum values of (R/S)-1 were calculated to be +2.9 × 10^–4 and −3.7 × 10^–4, respectively (Figure S5). Collectively, these results unambiguously demonstrate that the chiral BINOL auxiliary effectively induced chirality in both the terphenyl unit and the [9]­CPP macrocycle.

2.

(a, b) (R/S)-3 and (R/S)-1 in V-T CD spectra. (c, d) CD spectra of (R/S)-3, (R/S)-1 in CHCl₃. (e) Percentage change of (S)-3 and (S)-1 at 377 nm and around 475 nm, respectively. (f, g) V-T CD spectra of (S)-3, (S)-1 in C₂H₂Cl₄. (h) Fitting of the thermodynamic parameters of (S)-1 using the van’t Hoff equation.

5.

(a) Optimized structure of (R)-1 and (R)-[6]­OMe-1 (CAM-B3LYP-631Gd level). (b) Simulated CD spectra of (R)-1 (pink solid line) and (R)-[6]­OMe-1 (cyan solid line) at the CAM-B3LYP-631Gd level (SMD = chloroform). (c) Natural transition orbital (NTO) analysis of the lowest-energy transition of (R)- 1 (414 nm). The percentage number indicates the weight percentage of the dominant orbitals of interest.

Inversion Kinetics

We next demonstrate the fast atropisomeric inversion kinetics of the system by variable-temperature NMR (VT-NMR). The kinetic process of (S)-1 was studied by VT-NMR in C₂D₂Cl₄ (Figure ). Between 303 and 383 K, the Ha₁ and Ha₂ signals of the peripheral benzene rings overlap, indicating rapid ring flipping on the NMR time scale. At 383 K, these protons appear as a sharp doublet. This observation is consistent with a fast atropisomeric “in–out” conformational process, with the inward-facing Ha₂ (“in”) and outward-facing Ha₁ (“out”) environments of the phenyl rings interconvert rapidly (Figure ). Because the rate of this conformational interconversion greatly exceeds the chemical-shift difference (k ≫ Δν), the in and out resonances are averaged into a single sharp doublet. Upon cooling, the rate of the atropisomeric interconversion decreases and the averaged signal progressively broadens, reaching coalescence at 283 K. At lower temperatures (particularly below 243 K), the in and out environments become long-lived on the NMR time scale and resolve into two distinct resonances, reflecting the suppression of motional averaging. Peak assignments for Ha₁ and Ha₂ were established using high-temperature ¹H NMR (393 K), ¹H–¹H COSY (293 K, 243 K), nuclear Overhauser effect (NOESY) spectra (243 K), and computational predictions (Figures S24–S28; detailed in the Supporting Information). From the coalescence temperature (T _C = 283.15 K) and the chemical-shift difference (Δν = 744 Hz at 243 K), the free energy barrier was calculated as ΔG ^‡ = 12.4 kcal mol^–1 using the coalescence method, , a value comparable to those reported for other strained nanohoops. To exclude intermolecular effects from enantiomeric pairing, additional VT-NMR experiments were conducted on a racemic mixture in C₂D₂Cl₄ (Figure S22). Further, no coalescence was observed in CD₂Cl₂ (Figure S23), indicating the kinetics of the racemization is solvent-dependent, presumably due to differences in solvent polarity and viscosity. Together, this study underscoring a system that combines thermodynamic conformational locking with dynamic interconversion characteristics.

3.

Partial V-T ¹H NMR spectra (600 MHz, C₂D₂Cl₄) of (S)-1.

Single-Crystal Analysis

Crystallographic analysis of (R)-1 unequivocally confirms strain-induced macrocyclic chirality. Light yellow, acicular crystals suitable for X-ray diffraction were obtained by slow vapor diffusion of diethyl ether into dichloromethane. Although the BINOL units could, in principle, adopt a same-side arrangement, this conformation is expected to be sterically disfavored. Accordingly, the thermodynamically preferred structure places the BINOL units on both sides of the hoop plane. As revealed by the crystal structure, the three BINOL units adopt an asymmetric tripod-like arrangement, with one above and two below the hoop plane. The structure reveals a near-circular [9]­CPP core with cavity dimensions of 12.35 × 12.76 × 12.08 ų (centroid-to-centroid, Figure a). In the solid state, (R)-1 pack in alternating four layers along the a-axis (Figure b), with interhoop π–π stacking, C–H···N hydrogen bond interactions, C–H···S hydrogen bond interactions, and C–H···π interactions (Figures S51–S54). Atomic force microscopy (AFM) measurements were performed on both the liquid-dispersed and single-crystal samples. The relevant results and discussion are provided in the Supporting Information (Figures S55–S57). The chiral [9]­CPP skeleton exhibits directional distortion under the steric influence of BINOL, resulting in symmetry breaking via asymmetric torsional bias (Figures S58 and S59)a phenomenon quantified and mechanistically dissected in the following computational analysis (vide infra).

4.

(a) ORTEP drawing of the X-ray crystal structure of (R)-1 (top view) at the 50% probability level. (b) Packing arrangements of (R)-1 within the crystal, depicted as a space-filling model. All hydrogen atoms were omitted for clarity in (a).

Origin of the Cotton Effect in the Visible Region

Computational modeling unequivocally establishes macrocyclic torsion, rather than BINOL chromophoric contributions, as the primary origin of the observed CD signal across 360–550 nm region. To isolate skeletal chiroptical response, we replaced the three BINOL units in the (R)-1 crystal structure with methoxy groups (Figure a) and simulated the CD spectra at the CAM-B3LYP-631Gd level of theory. The simulated CD spectrum of the (R)-[6]­OMe-1 reproduces the Cotton couplet of (R)-1 with near-quantitative agreement (Figure a,b). Natural transition orbital (NTO) analysis reveals that the S₀ → S₁ excitation (HONTO → LUNTO) is localized exclusively on the torsionally distorted [9]­CPP backbone (Figure c), with the remaining contributions (37%) also confined to the CPP scaffold (Figures S65 and S66). The HONTO exhibits a helical nodal pattern across alternating phenylene units induced by macrocyclic torsion, whereas the LUNTO is concentrated on the benzothiadiazole acceptor, facilitating intramolecular charge transfer along the chiral π-scaffold independent of BINOL or methoxy substituents. Therefore, the emergent lowest-energy transition arises from topologically enforced orbital alignment within the strained nanohoop, directed by BINOL steric effects.

Conclusions

In conclusion, this work introduces a platform for dynamically chiral materials to achieve unprecedented thermodynamic conformational locking by harnessing the rigidity of cycloparaphenylenes. Through external chiral induction with BINOL auxiliaries, we generated a strained [9]­CPP nanohoop exhibiting the lowest-energy conformer while preserving rapid interconversion kinetics. The resulting system displays exceptional chiroptical robustness, with minimal CD signal variation across solvents and temperatures, in stark contrast to that of conventional helicene-based dynamically chiral materials. Comprehensive spectroscopic, crystallographic, and computational evidence unambiguously demonstrate that the intense Cotton effects arise from torsionally distorted CPP-centered transitions. By expanding dynamic chirality beyond traditional scaffolds and imparting dynamic chirality stability, this CPP-based approach overcomes the limitations of temperature/solvent sensitivity and structural uniformity. These results open avenues to robust chiral optoelectronics and tunable chiroptical properties enabled by dynamic chirality.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.6c01002.

• Procedures, characterization data, crystal data, and calculation details (PDF)

§.

Z.Z. and Q.S. contributed equally to this work. Z.J. conceived and oversaw the research. Z.Z. and Q.S. designed the synthesis routes and conducted the experiments. Z.M. performed the theoretical calculation. Q.S. contributed to starting materials preparation. X.M. carried out single-crystal X-ray analysis. Z.Z. and Z.J. wrote and edited the manuscript.

The authors declare no competing financial interest.