Controlled interconversion of macrocyclic atropisomers via defined intermediates

Rotations about C–C single (σ) bonds shape the three-dimensional structures of biomolecules and influence function, and simple σ-bond rotations are well understood. However, cooperative multi-bond rotations, common in complex chemical and biological systems and central to molecular machines and stimuli-responsive systems, remain less explored. Synthetic macrocycles often interconvert rapidly, hindering kinetic study, and slow, reversible conformational exchange without external guests is rare. The authors aim to create and study a macrocyclic system that undergoes slow, controllable atropisomerization via cooperative σ-bond rotations, enabling capture and characterization of intermediates and revealing how solvent and chemical environment control interconversion. They report a macrocycle (OC-4) existing as distinct atropisomers (C2v and C4-symmetric forms) at ambient temperature and show controlled interconversion via a defined intermediate, with implications for design of molecular machines and host–guest systems.

Prior work established control of single-bond rotations and developed molecular machines responsive to chemical, electrochemical, and photochemical stimuli. Atropisomeric macrocycles that switch conformation under stimuli include cycloarylenes, resorcinarenes, biphen[n]arenes, polycyclic peptides, and amide naphthotubes. Yet, most synthetic macrocycles exhibit fast interconversion, complicating kinetic analysis; slow exchange processes and reversible σ-bond rotation between stable and metastable atropisomers are rarely reported. Studies of conformational interconversion in host–guest recognition exist, but capturing intermediates during multi-σ-bond rotations is uncommon. This work builds on these gaps by creating a system with experimentally observable, isolable intermediates during atropisomerization and by dissecting solvent and counterion effects.

Synthesis: OC-4 was synthesized via fragment coupling followed by a Suzuki–Miyaura reaction (CsF, Pd(dppf)2Cl2·CH2Cl2). Conditions: toluene, 373 K (12 h) afforded predominantly the C4-symmetric isomer (31% yield; C2-symmetric trace). In acetonitrile, 333 K (48 h), both C2- and C4-isomers were isolated (7% and 8% yields). Semiempirical PM7 calculations indicated C4 is more stable than C2; cyclization intermediates (Cs-OC-4-im vs C2v-OC-4-im) formation heat suggested C2v is kinetic at lower temperature. Characterization: 1H/13C NMR, COSY, NOESY in TCE-d2 (298 K). MALDI-TOF HRMS [M+Na]+ m/z calcd 1207.4092; found 1207.4080 (C2v), 1207.4083 (C4). Single-crystal X-ray diffraction (SCXRD) from CH2Cl2/cyclohexane (1:1) revealed C2v-OC-4 with parallel meso-dimethylbenzene sets, ester groups outward (cavity ~7.8 Å; torsion 57–63°), and C4-OC-4 in 1,3-alternate-like conformation with ester groups on one side (cavity ~8.7 Å; inter-ring 84–112°). Thermal/solvent conversion studies: Variable-temperature 1H NMR (TCE-d2, 5.0 mM) from 233–373 K showed both isomers stable below 343 K; interconversion observed ≥343 K. In toluene-d8, conversion of C2v to C4 begins at 318 K; >373 K leads to near-complete conversion to C4 and other forms, indicating a strong solvent effect. Kinetic monitoring: Time-dependent 1H NMR at 393 K in TCE-d2 (5.0 mM) starting from C2v tracked populations of C2v, C4, and intermediates (Cr, Cs, C2-like). In toluene-d8 at 373 K (1.0 mM), conversion was faster and more complete; the same experiment in TCE-d2 at 373 K gave lower conversion at equal time and concentration. Empirical equations (derived from spectral integrations) modeled concentration versus time and enabled extraction of equilibrium constants, rate constants, and free energies (see Supplementary eqs. 1–25). Intermediate capture: After heating C2v-OC-4 in TCE-d2 at 393 K for 15 min to maximize intermediate content, solvent was removed under airflow at constant temperature; the residue was dissolved in CH2Cl2/MeOH (1:1) and allowed to slowly evaporate (298 K, 1 day). SCXRD from the resulting crystals identified C2v-, C4-, and a Cs-symmetric intermediate (C1-OC-4). Micro-isolation of C1 crystals (<0.1 mg), washing, drying, and dissolution in TCE-d2 enabled 1H, COSY, NOESY (298 K). Minor pseudo-C2 and Cs isomers coexisted by NMR; PM7 supported their relative energies and small interconversion barriers. Intermediate thermolysis: C1-OC-4 in TCE-d2 at 393 K showed time-dependent redistribution toward predominantly C4 (final ~76%), with transient C2 population maxima and minor C3/C2-like species. In toluene-d8 at 373 K for 12 h, little change occurred, indicating irreversibility under these conditions. Chemical interconversion: C4-OC-4 was hydrolyzed with MOH (M = Li, Na, K, Rb, Cs) or TBAH in EtOH/H2O (1:1), reflux 24 h, acidified (pH 3) to yield CA-4 mixtures (various isomers). Without purification, re-esterification with TBAF (THF) and CH3I (RT, 48 h) afforded OC-4 mixtures. Countercation strongly influenced final isomer ratios: NaOH, KOH, RbOH favored higher C2 yields; TBAH promoted high C1 yield. Single crystals from NaOH/KOH conditions yielded structural insight into a mixed-ion complex [[C2-CA-4-3H]− Na+ K+ 3Cl− DMF] with hydronium solvation and bridging K+ coordination; SCXRD also obtained [C4-CA-4-2DMF-H2O]. Calculations rationalized cation-dependent stabilization. Host–guest studies: Binding of linear guests 1,8-dibromooctane (G1), octane-1,8-dithiol (G2), 1,9-decadiyne (G3), and n-eicosane (G4) examined by 1H NMR (CDCl3/CD3OD 1:2). C2v showed negligible binding; C4 showed clear shifts. Job plots supported 1:1 stoichiometry (G1–G3). ESI-HRMS confirmed complexes. Association constants: Ka (C4·G1) = 4.7 ± 0.5 M−1; Ka (C4·G2) = (6.2 ± 0.6) × 10^3 M−1; Ka (C4·G3) = (6.0 ± 0.6) × 10^3 M−1. SCXRD revealed [C4-OC-4·G1], [C4-OC-4·G2], [C4-OC-4·G3], and a [3]pseudo-rotaxane 2(C4-OC-4)·n-eicosane with ~3.8 Å C···C contacts consistent with C–H···π interactions. Fullerene binding: In TCE-d2, C4-OC-4 bound C60 and C70 (1:1 stoichiometry) with Ka = (5.9 ± 0.6) × 10^3 M−1 (C60) and (5.2 ± 0.5) × 10^3 M−1 (C70) by 1H NMR; UV–vis titrations gave (2.4 ± 0.2) × 10^3 and (2.2 ± 0.2) × 10^3 M−1, respectively. MALDI-TOF HRMS supported complex formation. SCXRD structures showed endo binding with ≤3.8 Å contacts, suggestive of π···π donor–acceptor interactions. Computation: MM+ and PM7 (HyperChem 8.0; MOPAC) evaluated relative energies of isomers and transition states. PM7 indicated C2 and C4 are more stable than C3; small barriers (≤10 kcal mol−1) between C1 and C2/C4. Potential energy profiles were constructed from experimental kinetics and theory. Instrumentation and crystallography: Multiple NMR spectrometers (400–700 MHz), HRMS (ESI, EI, MALDI-TOF), UV–vis, and diffractometers (Saturn724+, SuperNova Dual Cu). Structures refined with SHELXL-2014/2018; data deposited at CCDC with listed deposition numbers.

- OC-4 exists at 298 K as two stable atropisomers: C2v-OC-4 (kinetic, metastable) and a C4-symmetric isomer (thermodynamic, more stable). PM7 calculations corroborate greater stability of the C4 form. - Synthesis outcomes: in toluene (373 K), C4-OC-4 obtained in 31% yield (C2v trace); in acetonitrile (333 K), C2v and C4 obtained in 7% and 8% yield, respectively. MALDI-TOF HRMS: [M+Na]+ found 1207.4080 (C2v), 1207.4083 (C4) versus calcd 1207.4092. - Solid-state structures: C2v-OC-4 shows parallel meso-dimethylbenzene units and outward esters with ~7.8 Å cavity; C4-OC-4 shows 1,3-alternate-like conformation with all esters to one side and ~8.7 Å cavity. - Thermal interconversion: In TCE-d2, both isomers are stable below 343 K; above this, interconversion occurs. In toluene-d8, C2v→C4 begins at 318 K and is strongly promoted; at ≥373 K, conversion approaches completion and appears irreversible under those conditions. - Kinetics (TCE-d2, 393 K, 5 mM starting from C2v): After 2 h, C4 reached ~71.4%, C2v ~5.6%, with intermediates rising to a maximum ~49.2% then decreasing to ~23.0% at equilibrium. Multiple intermediates (Cr, Cs, C2-like) were inferred and modeled; empirical equations fitted time courses and yielded K, k, ΔG°, and ΔG‡ (Table 1). Potential energy analysis indicates small barriers (≤10 kcal mol−1) between key forms. - Intermediate capture: A Cs-symmetric intermediate (C1-OC-4) was isolated and structurally characterized by SCXRD; solution NMR showed minor coexistence with pseudo-C2 and Cs species. Upon heating C1 in TCE-d2 (393 K), equilibrium mixtures enriched in C4 (~76%) form. - Chemical promotion of reverse conversion: Hydrolysis of C4-OC-4 to CA-4 with MOH/TBAH followed by re-esterification (TBAF/CH3I) yields OC-4 mixtures with strong countercation dependence. NaOH, KOH, RbOH favor higher C2 yields (e.g., C2 up to ~70.5% with NaOH), while TBAH favors C1 (~50.3%) and C2 (~33.6%). These conversions surpass simple thermal conversion of C4 in TCE-d2 at 393 K (28.4%). SCXRD revealed a mixed-ion complex [[C2-CA-4-3H]− Na+ K+ 3Cl− DMF] and [C4-CA-4-2DMF-H2O], rationalizing cation effects. - Host–guest recognition: C4-OC-4 forms 1:1 pseudo-rotaxane complexes with linear guests (G1–G3) with Ka values: 4.7 ± 0.5 M−1 (G1), (6.2 ± 0.6) × 10^3 M−1 (G2), (6.0 ± 0.6) × 10^3 M−1 (G3), and a [3]pseudo-rotaxane with n-eicosane. SCXRD confirmed threading and ~3.8 Å contacts. C4-OC-4 binds fullerenes with Ka = (5.9 ± 0.6) × 10^3 M−1 (C60) and (5.2 ± 0.5) × 10^3 M−1 (C70) by NMR; UV–vis gave ~2.4 × 10^3 and ~2.2 × 10^3 M−1. C2v-OC-4 showed negligible binding to these guests.

The study demonstrates controlled, stepwise atropisomerization in a macrocycle through cooperative σ-bond rotations, moving from a kinetic C2v form to a thermodynamically favored C4 form via isolable Cs-symmetric intermediates. Solvent plays a decisive role: toluene-d8 lowers the onset temperature and drives conversion toward C4 with apparent irreversibility, while TCE-d2 supports reversible, slower exchange that enables kinetic analysis and intermediate capture. Chemical transformations (hydrolysis/re-esterification) provide an orthogonal control modality, enabling conversion from the stable C4 back to metastable C2 and Cs forms with strong countercation effects, consistent with cation-stabilized carboxylate arrangements observed crystallographically and supported computationally. These conformational states exhibit distinct recognition properties: the more open C4 macrocycle acts as a host for linear guests and fullerenes, whereas C2v lacks appreciable binding under similar conditions. The ability to capture intermediates, quantify kinetics, and switch recognition behavior via solvent and counterions advances understanding of coupled σ-bond rotations and offers design principles for stimuli-responsive molecular machines and smart materials.

This work establishes a macrocyclic platform (OC-4) that undergoes controlled interconversion between stable atropisomers through defined, isolable intermediates. The kinetic C2v form converts thermally to the thermodynamic C4 form, with solvent markedly affecting rates and reversibility; an intermediate Cs form (C1) was captured and structurally characterized. Chemical hydrolysis/re-esterification enables reverse conversion from C4 to higher-energy C2/Cs states with countercation-controlled selectivity. Distinct host–guest behaviors arise from the different conformations: C4 binds linear chains as pseudo-rotaxanes and encapsulates C60/C70, whereas C2v shows minimal binding. These insights into multi-σ-bond rotational landscapes, solvent/cation effects, and structure–function relationships will guide the design of molecular machines and adaptive materials. Future work could map full energy landscapes with higher-level computations, achieve catalytic or light-driven control of interconversion, and integrate such macrocycles into device architectures.

The study’s kinetic and thermodynamic analyses rely on semiempirical (PM7) calculations and empirical fitting of NMR time courses; higher-level computational methods could refine energy barriers and transition states. Isolation of the Cs intermediate required delicate crystallization and yielded very small quantities (<0.1 mg), limiting comprehensive solution studies. Solubility constraints (e.g., low solubility in toluene-d8) imposed concentration differences across solvents and may influence observed kinetics. Apparent irreversibility in toluene-d8 restricts direct comparison of reversible dynamics across solvents. Some spectral assignments involve overlapping signals and inference of minor species, introducing uncertainty in speciation at low abundance.