Kinetic Control of Threading and Dethreading in Linked Rotaxanes via Hydrogen Bonding

Abstract

The kinetic control of macrocyclic motions is a key aspect of mechanically interlocked molecules (MIMs). Although hydrogen bonding (H‐bonding) offers a high reversibility and selectivity, the use of neutral H‐bonding to control the macrocyclic mobility remains limited. In this study, the effects of H‐bonding on the threading and dethreading kinetics of linked rotaxanes containing a permethylated α‐cyclodextrin unit and an aniline moiety were investigated. UV–vis spectroscopy revealed significantly reduced reaction rates in H‐bond acceptor solvents, such as dimethyl sulfoxide (DMSO) and N,N‐dimethyl formamide. NMR titrations and FT‐IR spectroscopic analyses confirmed that H‐bonding between the aniline moiety and these solvents acts as a “brake” during threading/dethreading. Moreover, Eyring plots indicated that enthalpic losses during H‐bond cleavage contribute to the increased activation barriers for these processes. Additionally, the introduction of H‐bond acceptors, such as DMSO and tributylphosphine oxide, effectively modulated these rates of threading and dethreading, highlighting the potential for controlling kinetic phenomena in MIM‐based systems.

Kinetic control of the macrocycle motions in linked rotaxanes was studied via hydrogen bonding. Rotaxanes bearing permethylated α‐cyclodextrin moieties exhibited reduced threading/dethreading rates in hydrogen bond acceptor solvents, such as DMSO. Spectroscopic analyses identified hydrogen bonding as a 'brake', with enthalpic losses increasing the activation barriers, thereby providing insights into kinetic control in mechanically interlocked molecules.

1. Introduction

Conformational and co‐conformational changes play an essential role in the chemistry of mechanically interlocked molecules (MIMs), which are based on the dynamic motions of macrocycles.^{[ 1} , ² , ³ , ⁴ , ⁵ , ^{6 ]} In rotaxane synthesis, the threading process between the ring and axle components is crucial, because this process creates entanglement among the MIMs.^{[ 1} , ⁷ , ⁸ , ^{9 ]} In addition, [2]rotaxane‐type molecular switching devices^{[ 10} , ¹¹ , ¹² , ^{13 ]} and [c2]daisy‐chain‐type actuators^{[ 14} , ¹⁵ , ^{16 ]} have been reported based on the shuttling motions of macrocycles. Furthermore, molecular pumps^{[ 17} , ¹⁸ , ¹⁹ , ²⁰ , ^{21 ]} and motors^{[ 5} , ¹⁹ , ²² , ²³ , ^{24 ]} have also been developed by controlling the kinetics of the threading and shuttling reactions of the ring components. Therefore, kinetic control of the macrocyclic motions in MIMs is an essential technique in the development of MIM‐based functional materials.

To date, many studies have revealed relationships between the chemical structures and macrocyclic motions of MIMs, including the relationship between the structures of the stopper moiety and the threading/dethreading rate,^{[ 9} , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ^{29 ]} and the relationship between the structure of the linker and the shuttling rate.^{[ 30} , ^{31 ]} Recently, control of the threading/dethreading and shuttling rates using stimuli‐responsive stoppers and linkers has been reported.^{[ 23} , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ^{37 ]} Moreover, kinetic control has been achieved by exploiting the solvent polarity,^{[ 38} , ³⁹ , ^{40 ]} metal coordination,^{[ 32 ]} Coulombic interactions,^{[ 33 ]} dynamic covalent bonds,^{[ 23 ]} E/Z photoisomerization,^{[ 34} , ^{35 ]} and redox reactions.^{[ 36} , ^{37 ]} Additionally, hydrogen bonding (H‐bonding) has emerged as a promising stimuli‐responsive motif, wherein the weakness of the H‐bonding interactions leads to high degrees of reversibility and selectivity.^{[ 41} , ^{42 ]} Methods for controlling the rate of macrocyclic motion via H‐bonding would therefore provide robust and unique MIM‐based materials that can be utilized even under mild conditions. However, reports into controlling the macrocyclic mobility using neutral H‐bonding interactions are quite limited.^{[ 43 ]}

As previously reported, linked rotaxanes bearing a permethylated α‐cyclodextrin (PM α‐CD) moiety and a diphenylacetylene (DPA) group exhibit an efficient insulation effect, and have been applied to molecular wires and luminescent materials.^{[ 44} , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ^{53 ]} The kinetic parameters for the threading and dethreading of these species in polar solvents were previously investigated, and the substituent effects of the capping moiety on the kinetic and thermodynamic parameters have been revealed.^{[ 54 ]} It was therefore envisaged that the interactions between substituents at the capping moiety and other molecules (e.g., solvents or additives) could have a significant effect on the threading/dethreading rate because the structural restrictions of linked rotaxanes force the threading/dethreading event to occur near the capping moiety.

Thus, in the current study, the effects of H‐bonding on the threading and de‐threading kinetics of linked rotaxanes containing a unit and an aniline moiety (a relatively weak H‐bond donor) are investigated (Figure 1).

Figure 1.

Schematic illustration of the intramolecular inclusion reaction, which occurs via the head pathway with cleavage of the NH₂ H‐bond. H‐bond cleavage increases the activation energy and decreases the reaction rate.

2. Results and Discussion

To investigate the inclusion phenomenon of the linked rotaxane, the donor–acceptor dyes un‐DA and in‐DA were selected as model compounds that exhibit different absorption spectra (Scheme 1).^{[ 55 ]} The syntheses of un‐DA and in‐DA were performed according to the literature.^{[ 55 ]} un‐DA was obtained by the reduction of a nitro group, followed by heating in a H₂O/MeOH mixture to yield in‐DA. Since the conversion between un‐DA and in‐DA requires heating, both compounds can be isolated at room temperature. For comparison, compounds un‐OH‐DA and in‐OH‐DA, which have an OH group in the capping moiety, were also synthesized (Scheme 1). Figure 2a shows the change in the UV–vis spectrum of in‐DA (blue plot) and the corresponding spectra recorded upon heating in toluene at 60 °C (gray and red plots). It can be seen that the spectra exhibit an isosbestic point, in addition to a redshift of the maximum absorption wavelength and an increase in absorbance. These spectral changes were attributed to the dethreading of in‐DA to form un‐DA due to the hydrophobic nature of toluene. Since these spectral changes reflect the kinetic and thermodynamic processes occurring during the threading/dethreading reactions, the threading and dethreading rates can both be calculated. Consequently, the threading/dethreading rates were determined by global fitting analysis of the UV–vis spectral changes (Figure 2b), and the threading rate constant (k _in) and dethreading rate constant (k _out) were determined to be 8.8 × 10⁻⁶ and 7.3 × 10⁻⁵ s⁻¹, respectively.

Scheme 1.

Chemical structures of un‐DA, in‐DA, un‐OH‐DA, and in‐OH‐DA.

Figure 2.

(a) UV–vis spectral changes of in‐DA upon heating in toluene at 333 K. The UV–vis spectrum of the generated un‐DA is also shown. (b) Change in the absorbance at 365 nm under the conditions of panel A and the corresponding fitting curve.

Comparable experiments were conducted to determine the values of k _in and k _out in 11 solvents, allowing calculation of the Gibbs free energy change (ΔG; representing the thermodynamic properties) and the half‐life (t _1/2; representing the kinetic properties), as detailed in Figure 3 and Table S1. ΔG was found to be negatively correlated with the solvent polarity parameter $E_{\mathrm{T}}^{\mathrm{N}}$ (Figure 3a).^{[ 56 ]} As a result, in a polar solvent, the insulated form would be enthalpically favorable due to the disadvantageous solvation of DPA and the advantageous interactions between DPA and the inner cavity of the PM α‐CD moiety.

Figure 3.

Relationships between (a) $E_{\mathrm{T}}^{\mathrm{N}}$ and ΔG, (b) $E_{\mathrm{T}}^{\mathrm{N}}$ and t _1/2, and (c) H‐bond acceptor parameters (β) and t _1/2 at 333 K. Tol: toluene, THF: tetrahydrofuran, DMF: N,N‐dimethyl formamide, EA: ethyl acetate, DMSO: dimethyl sulfoxide, ACN: acetonitrile, IPA: isopropanol, EtOH: ethanol, MeOH; methanol.

In contrast to the thermodynamic parameter ΔG, the kinetic parameter t _1/2 does not correlate with $E_{\mathrm{T}}^{\mathrm{N}}$ (Figure 3b). The typical value of t _1/2 was determined to range from 1–3 h, whereas the t _1/2 values obtained in N,N‐dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO) were 7 and 18 h, respectively. Similar trends were observed for the in/un‐OH‐DA system, wherein the axle contains a hydroxyl group instead of an amino group (Figures S3–S6, Table S2).

To elucidate the causes of the abnormal t _1/2 values in DMF and DMSO, ¹H NMR spectroscopy titration experiments were performed (Figure 4). Upon the addition of DMSO‐d ₆ to a 1 mmol L⁻¹ in‐DA solution in toluene‐d ₈, the protons close to the amino group (a, b) exhibited a significant downfield shift, suggesting the presence of interactions between the amino group and DMSO‐d ₆ (Figure 4a and S7). Fitting analysis performed assuming a 1:1 binding model revealed a small association constant (Figure 4B, K = 5.1 ± 0.2 mol⁻¹ L). These results indicate that the weak interaction consists of H‐bonding between the amino group (a weak H‐bond donor) and DMSO (a strong H‐bond acceptor).^{[ 57 ]} In addition, the FT‐IR spectra were recorded for in‐DA in the presence and absence of DMSO. Notably, the addition of DMSO led to a shift in the absorption peaks of the of N─H stretching vibrations from 3358 to 3336 cm⁻¹ and from 3246 to 3230 cm⁻¹, demonstrating the existence of H‐bonding between the amino group of in‐DA and DMSO (Figure S9).^{[ 58 ]} These results demonstrate that the abnormally slow threading/dethreading reactions in DMF and DMSO are caused by H‐bonding between the axle amino group and H‐bond acceptor solvents, as indicated by their high H‐bond acceptor parameters (DMF: β = 8.3, DMSO: β = 8.9).^{[ 57 ]} Ultimately, such H‐bonding acts as a “brake” on the threading/dethreading reactions. Due to the structural restrictions of the linked rotaxane structure, the threading/dethreading events occur near the capping moiety. Therefore, the interactions between substituents at the capping moiety and other molecules have a significant impact on the threading/dethreading rate.

Figure 4.

(a) Changes in the chemical shifts of the protons of in‐DA upon the addition of 1.2 mol L⁻¹ DMSO. (b) Change in the chemical shift the H_a proton of in‐DA upon the addition of various amounts of DMSO.

To investigate the effect of H‐bond acceptors in greater detail, the threading/dethreading reactions were monitored in toluene and DMSO at 333–353 K, and Eyring plots of k _out were created (Table 1, Figure S2). The Gibbs free energy of activation (ΔG ^‡) for the dethreading of in‐DA at 333 K in toluene was determined to be 108.3 ± 6.0 kJ mol⁻¹ (with a 2σ error), while that in DMSO was determined to be 115.1 ± 3.3 kJ mol⁻¹, corresponding to the longer t _1/2 observed in DMSO. A similar trend was observed for the dethreading of in‐OH‐DA (105.3 in kJ mol⁻¹ in toluene and 111.1 kJ mol⁻¹ in DMSO), suggesting that the deceleration effect is caused by the same phenomenon. Comparing the ΔH ^‡ and−TΔS ^‡ values recorded in toluene and DMSO, where ΔH ^‡ is the enthalpy of activation and ΔS ^‡ is the entropy of activation, the value of ΔH ^‡ in DMSO was found to be 17.5 ± 4.9 kJ mol⁻¹ larger than that in toluene, while the value of −TΔS ^‡ in DMSO was determined to be 10.6 ± 4.8 kJ mol⁻¹ lower. These results indicate that the large ΔG ^‡ observed in DMSO is caused by the enthalpic loss associated with H‐bond cleavage during the threading/dethreading reactions (Figure 1).

Table 1.

ΔH ^‡, −TΔS ^‡, and ΔG ^‡ (T = 333 K for −TΔS ^‡ and ΔG ^‡) values determined for the dethreading reactions of in‐DA and in‐OH‐DA in toluene and DMSO. The corresponding 2σ errors are also provided.

	Solvent	ΔH ‡ / kJ mol−1	−TΔS ‡ / kJ mol−1	ΔG ‡ / kJ mol−1
in‐DA	Toluene	89.1 ± 2.4	19.1 ± 2.3	108.3 ± 6.0
	DMSO	106.6 ± 4.3	8.5 ± 4.2	115.1 ± 3.3
in‐OH‐DA	Toluene	– a )	– a )	105.3
	DMSO	– a )	– a )	111.1

^a) Not determined.

Additionally, control of the threading/dethreading rates was attempted using H‐bond‐acceptor additives, namely DMSO (β = 8.9) and tributylphosphine oxide (TBPO, β = 9.9).^{[ 57 ]} The t _1/2 values of the threading/dethreading reactions in toluene alone and in the presence of each additive were determined by monitoring the changes in the UV–vis spectra. Both H‐bond acceptors were found to increase the value of t _1/2 (Figure 5). More specifically, in a 10 % solution of DMSO t _1/2 was determined to be 4.5 h, while the corresponding value in a 1.0 mol L⁻¹ solution of TBPO was defined as 12 h. This difference between DMSO and TBPO was attributed to their differing abilities to form H‐bonds.

Figure 5.

Values of t _1/2 of the dethreading reaction of un‐DA recorded in toluene upon the addition of DMSO and TBPO at 333 K.

Finally, it was demonstrated that the slowed dethreading reaction rate could be recovered by the addition of 2,2,2‐trifluoroethanol (TFE) as an H‐bond donor (Figure 6 and S8). More specifically, in toluene‐d ₈, the t _1/2 value of dethreading was determined to be 23.9 h. In contrast, upon the addition of a 0.31 M TBPO solution in toluene‐d ₈, the value of t _1/2 was significantly extended to >1000 h due to the formation of an H‐bond between TBPO and in/un‐DA. Upon the addition of TFE (2.1 eq., α = 3.7),^{[ 57 ]} the dethreading rate increased, with t _1/2 shortening to 68.6 h due to the strong H‐bonding between TBPO and TFE. These results indicate that neutral hydrogen bonding can effectively regulate the kinetics of threading and dethreading reactions in the linked rotaxane system.

Figure 6.

Changes in [un‐DA]/([un‐DA]+[in‐DA]) in a 0.31 M TBPO solution in toluene‐d ₈ before and after the addition of TFE (2.1 eq.) at 313 K.

3. Conclusion

In this work, control of the kinetic properties of linked rotaxanes was demonstrated via hydrogen bonding (H‐bonding). For this purpose, the threading/dethreading reactions of linked rotaxanes containing amino groups were investigated in various solvents. It was found that although the thermodynamic parameter ΔG depended on the solvent polarity, the kinetic parameter t _1/2 did not correlate with the solvent polarity, and exhibited exceptionally long values in DMF and DMSO. ¹H NMR titration experiments and FT‐IR spectroscopy revealed that the abnormal behavior of t _1/2 can be explained by considering the H‐bonds between the axle amino group and the H‐bond acceptor solvent. Analysis using Eyring plots indicated that the enthalpic loss associated with H‐bond cleavage during the threading/dethreading reactions leads to a large ΔG ^‡ and a long t _1/2. Furthermore, the addition of H‐bond acceptors increased the t _1/2 values of the threading/dethreading reactions. Overall, this strategy aimed at controlling the kinetics of MIMs via H‐bonding is expected to pave the way for the development of sophisticated MIM‐based materials.

Supporting Information

The authors have cited additional references within the Supporting Information.^{[ 59} , ⁶⁰ , ⁶¹ , ^{62 ]}

Conflict of Interests

The authors declare no conflict of interest.

Supporting information

Supporting Information

Miyagishi H. V., Yamaguchi S., Tsuda S., Masai H., Terao J., Chemistry - An Asian Journal. 2025, e202500302. 10.1002/asia.202500302

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.