Controlled interconversion of macrocyclic atropisomers via defined intermediates

Rotations around C-C single bonds significantly impact the 3D structures and biological activities of molecules like DNA and proteins. While single bond rotations are well-understood, cooperative rotations involving multiple bonds are less explored, despite their prevalence in chemical and biological systems. Control over these multi-bond rotations often relies on external stimuli such as chemical, electrochemical, or photochemical triggers. Convertible atropisomeric macrocycles, which change conformation upon external stimulus, have been reported, including cycloarylenes, resorcinarenes, and others. However, studying slow conformational conversions in macrocycles is challenging due to fast exchange processes. While conformational interconversions have been investigated in molecular recognition, slow conversions are rare. The development of such systems is crucial for molecular machines and devices, as well as understanding host-guest binding mechanisms. Reversible conformational transformations without added species remain challenging, particularly reversible σ bond rotation-based conversions between stable and metastable atropisomer states. This study aims to address this gap by investigating a novel macrocycle and its conformational interconversion.

The paper reviews existing literature on the impact of C-C single bond rotations on molecular structure and function, focusing on the challenges associated with studying cooperative rotations in multiple bonds. It highlights the use of external stimuli to control such rotations in synthetic systems and mentions examples of convertible atropisomeric macrocycles reported previously, including cycloarylenes, resorcinarenes, biphen[n]arene, polycyclic peptides, and amide naphthotube. The authors emphasize the rarity of slow conformational exchange systems in macrocycles and their potential applications in molecular machines and the analysis of host-guest interactions. The lack of research on reversible σ bond rotation-based conversions between stable and metastable atropisomer states is also underscored.

The macrocycle octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4) was synthesized via a combined fragment coupling and Suzuki-Miyaura reaction. Different reaction conditions (toluene at 373 K and acetonitrile at 333 K) yielded varying ratios of *C*_2v-OC-4 and *C*_4h-OC-4 atropisomers. The isomers were characterized using ¹H and ¹³C NMR spectroscopy, COSY, NOESY, and MALDI-TOF HRMS. Single crystal X-ray diffraction confirmed the *C*_2v and *C*_4h symmetries, revealing structural details like cavity diameters and torsion angles between benzene rings. Thermal conversion studies using temperature-dependent ¹H NMR spectroscopy in TCE-d₂ and toluene-d₈ investigated isomerization kinetics. Time-dependent ¹H NMR analyses at 393 K in TCE-d₂ revealed the formation of intermediates with C_r, C_s, and C₂ symmetries. A Cs-symmetric intermediate (*C_s*-OC-4) was isolated and characterized using single crystal X-ray diffraction and NMR spectroscopy. Kinetic modeling of the isomerization process provided rate constants and thermodynamic parameters. Chemical reactions, including hydrolysis using various MOH salts (M = Li, Na, K, Rb, Cs) and TBAH followed by esterification, were used to promote conversion of *C*_4h-OC-4 to *C*_2v-OC-4 and *C_s*-OC-4. The influence of countercations on the conversion was studied. Host-guest interaction studies using linear guests (1,8-dibromooctane, octane-1,8-di-thiol, 1,9-decadiyne, and n-eicosane) and fullerenes (C₆₀ and C₇₀) were conducted using ¹H NMR spectroscopy, Job plots, ESI-HRMS, and single crystal X-ray diffraction. Theoretical calculations (PM7 and MM+) were used to support experimental findings and analyze energetics.

The study successfully synthesized and characterized the macrocycle OC-4, which exists as two stable atropisomers (*C*_2v-OC-4 and *C*_4h-OC-4) at room temperature. Heating induced a stepwise conversion of the thermodynamically more stable *C*_4h-OC-4 to the kinetic product *C*_2v-OC-4, proceeding through a previously unobserved *C_s*-symmetric intermediate. This intermediate (*C_s*-OC-4) was isolated and structurally characterized. The solvent significantly impacted the conversion rate, with toluene-d₈ promoting faster conversion compared to TCE-d₂. Hydrolysis of *C*_4h-OC-4 to its acid form (CA-4), followed by re-esterification, provided a chemically controlled route to interconvert the atropisomers, with countercation effects observed. Importantly, *C*_4h-OC-4 showed significantly different host-guest properties compared to *C*_2v-OC-4, exhibiting efficient binding to linear guests to form pseudo-rotaxanes and to fullerenes (C₆₀ and C₇₀). The binding stoichiometry and association constants were determined. The single crystal structures of the complexes formed with linear guests and fullerenes were also elucidated. Theoretical calculations supported the experimental observations, providing insights into the energy barriers and relative stabilities of different conformations. The kinetic modeling of the interconversion provided rate constants and thermodynamic parameters.

The findings demonstrate a controlled and reversible interconversion of macrocyclic atropisomers via a defined intermediate. This is a significant advancement in understanding cooperative multi-bond rotations. The observation of a stable intermediate species during the atropisomerization process provides a detailed mechanistic insight into this complex process. The solvent effects and countercation dependence highlight the importance of environmental factors in influencing conformational changes. The differences in host-guest properties between the two atropisomers showcase the potential of conformational control for tuning molecular recognition abilities. This research has implications for the design and synthesis of stimuli-responsive molecules and molecular machines, including molecular motors and devices.

This study successfully demonstrated the controlled interconversion of macrocyclic atropisomers through a defined intermediate, providing valuable insights into cooperative multi-bond rotations. The ability to control the conformational switching through both thermal and chemical methods opens exciting avenues for the design of functional materials. Further research could explore the potential applications of these findings in the development of molecular machines and stimuli-responsive smart materials. Investigating other macrocycles with similar conformational properties could further broaden our understanding of this phenomenon.

The study focuses on a specific macrocycle; the generality of the findings to other systems requires further investigation. The kinetic modeling relies on certain assumptions, and the accuracy of the parameters might depend on the validity of these assumptions. The synthesis yields of some intermediates are low, which might hamper further studies requiring larger quantities. The range of guests used in the host-guest experiments is limited, and a broader study is needed to fully understand the selectivity and binding preferences of the macrocycle.