# Study of [2]- and [3]Rotaxanes Obtained by Post-Synthetic Aminolysis of a Kinetically Stable Carbonate-Containing Pseudorotaxane

Philip Waelès, Maxime Gauthier, Frédéric Coutrot

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Philip Waelès, Maxime Gauthier, Frédéric Coutrot. Study of [2]- and [3]Rotaxanes Obtained by Post-Synthetic Aminolysis of a Kinetically Stable Carbonate-Containing Pseudorotaxane. European Journal of Organic Chemistry, 2022, 2022 (21), pp.e202101385. 10.1002/ejoc.202101385. hal-04117929

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# Study of [2]- and [3]Rotaxanes Obtained by Post-Synthetic Aminolysis of a Kinetically Stable Carbonate-Containing Pseudorotaxane

Philip Waelès,[a] Maxime Gauthier,[a] and Frédéric Coutrot*[a]

Here is reported the synthesis and study of dibenzo-24-crown-8 (DB24C8)-based [2]- and [3]rotaxanes that contain an ammonium as the best molecular station and carbamate moieties as secondary molecular stations. The common post-interlocking synthesis relies on the aminolysis of the *N*-succinimidyl carbonate extremity of an activated though insulated pseudorotaxane. The *N*-succinimidyl carbonate-based thread's extremity proved to be small enough to allow the slow slippage of the DB24C8 around the thread and large enough to

allow insulation of the kinetically stable pseudorotaxane. Due to its sensitivity towards amine compounds, the activated carbonate end of the encircled thread allowed post-interlocking aminolysis-based conversion into mechanically interlocked rotaxanes by providing the same way the carbamate secondary station for the DB24C8 in the thread backbone. Translation of the DB24C8 along the threaded axle between the two molecular stations was investigated.

## Introduction

Since the synthesis of the first interlocked molecules – a catenane[1] – the advent of supramolecular[2] chemistry, then the template-directed synthesis[3] made easier the chemical access to interlocked molecules. [2]rotaxanes belong to this class of fascinating compounds: they consist of a macrocycle that surrounds a molecular axle without being covalently linked to it. The mechanically interlocked architecture is ensured by the presence of stoppers at each extremity of the threaded axle that prevent the macrocycle from clearing off the thread. The possibility to incorporate several sites of interactions for the surrounding macrocycle – i.e. molecular stations – in the threaded axle of rotaxanes gave the opportunity to conceive molecular shuttles.[4] Several co-conformers may coexist in these latter, and their relative ratio closely depends on both the affinity of the molecular stations for the surrounding macro-cycle and steric effects.[5] The control of the localization of the macrocycle along the encircled thread may be possible if the affinities between stations and macrocycle are different. Alter-ing the affinities through chemical or physical *stimuli*,[6] or destabilizing a station-macrocycle complex through intermolec-ular interaction,[5c,7] afforded a wide range of responsive rotaxanes molecular shuttles in the literature until now, with

multiple miscellaneous applications.[8] In the past years, we have been focusing on the synthesis of several DB24C8-based rotaxane molecular shuttles based on triazolium,[9] pyridinium amide,[10] amide,[11] Weinreb amide,[5b,d] amine and ketone[5d] moieties as more or less efficient secondary molecular stations for the DB24C8. Recently, we proposed the *N*-hydroxysuccinimide[5a,12] (NHS) and its NHS ester derivative[11,13] as thread's pseudo stoppers that allowed slippage of the DB24C8, on the one hand, and subsequent post-synthetic[14] stopper exchange[5a,c,12a-b,13a,15] of rotaxane threads on the other hand. More precisely, NHS ester rotaxane building block was utilized as a precursor of a two-station molecular shuttle containing a triazolium secondary station for the DB24C8.[13a] Here, we propose the synthesis and insulation of the activated *N*-succinimidyl carbonate-containing pseudorotaxane and its post-synthetic transformation through aminolysis into [2]- and [3]rotaxanes that contain a carbamate[16] secondary site of interaction for the DB24C8. Further ¹H NMR studies showed the possibility for the DB24C8 to move from the ammonium site, at acidic medium, towards the carbamate site after deprotonation-then-carbamoylation of the ammonium moiety.

## Results and Discussion

Uncomplexed thread **1 u**[17] contained the ammonium template[18] that drove the pseudorotaxane self-assembly thanks to its binding affinity for the DB24C8 (Scheme 1). It also contained a bulky *m*-xylyl stopper at one extremity of the thread and a *N*-succinimidyl carbonate at the other. The size of thread's succinimidyl moiety, which is close to that of the cavity of the DB24C8,[12–13] allowed for the threading of the structure, though according to a slow process – called slippage – that is hampered by steric hindrance (Figure 1). Slipping-on reaction to obtain pseudorotaxane **1** was carried out at 60°C by mixing

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<footnote>[a] Dr. P. Waelès, Dr. M. Gauthier, Dr. F. Coutrot
Supramolecular Machines and Architectures Team, IBMM, Univ Montpellier, CNRS, ENSCM, Montpellier, France
E-mail: frederic.coutrot@umontpellier.fr
www.glycorotaxane.fr</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202101385</footnote>

<footnote>Part of the "Institute Feature IBMM" Special Collection.</footnote>

<footnote>© 2022 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</footnote>
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<figure><img src="image_7.png" /><figcaption>**Figure 1.** Plots of: (a) Conversion rate of thread **1 u** into pseudorotaxane **1** over time in CD₃CN at 333 K. Initial concentrations of **1 u** and DB24C8 are [**1 u**]₀ = 3.10⁻² M and [DB24C8]₀ = 9.10⁻² M; (b) {1/([DB24C8]₀-[**1 u**]₀)}.In (((**1 u**]₀.[DB24C8]₀-[**1**])/([DB24C8]₀.[**1 u**]₀-[**1**])) versus time for the slipping-on second-order process formation of pseudorotaxane **1** in CD₃CN at 333 K.</figcaption></figure>

1 equiv. of thread **1 u** with 3 equiv. of DB24C8 in the hydrogen bond promoting solvent acetonitrile. The concentrations of the different species during the slipping-on process were determined thanks to ¹H NMR spectroscopy (see Figure S8 of the SI). Kinetic rate of the slipping-on of the DB24C8 over the N-succinimidyl carbonate of **1 u** (initial concentrations [**1 u**]₀ = 3.10⁻² M, [DB24C8]₀ = 9.10⁻² M) was studied in acetonitrile at 60 °C and thermodynamic data deduced. Plots corresponding to the conversion yield of **1 u** into pseudorotaxane **1** over time is reported Figure 1a. The equilibrium was reached after about 12 days and a conversion yield of 66% of pseudorotaxane **1** was evidenced by ¹H NMR after this time.[¹⁹]

The thermodynamic constant K = 27.7 M⁻¹ was determined from the concentration of the molecular species at the equilibrium. From this value was calculated the free Gibbs energy of the slipping-on reaction ΔG°(CD₃CN, 333 K) =

-RTlnK = -9.2 kJ.mol⁻¹. Calculated values {1/([DB24C8]₀-[**1 u**]₀)}.In{([**1 u**]₀.[DB24C8]₀-[**1**])/([DB24C8]₀.[**1 u**]₀-[**1**])} versus t provided a linear curve (with a linear regression R² = 0.994), which demonstrated the second order of the slipping-on reaction (Figure 1b). A second order kinetic constant k_on of 3.10⁻⁵ M⁻¹.s⁻¹ was determined for the slipping-on process of thread **1 u** into pseudorotaxane **1**, by calculating the slope value of the linear curve from the equation k_on·t = {1/([DB24C8]₀-[**1 u**]₀)}.In{([**1 u**]₀.[DB24C8]₀-[**1**])/([DB24C8]₀.[**1 u**]₀-[**1**])}.[²⁰] The free enthalpy of activation ΔG⁺ₐon was extracted from the k_on value using the Eyring equation ΔG⁺ₐon = -RTln(k_on·h/k_b·T), where R, h and k_b correspond respectively to gas, Planck and Boltzmann constants. At 333 K in CD₃CN, a free enthalpy of activation ΔG⁺ₐon = 110.7 kJ.mol⁻¹ was calculated.

Pseudorotaxane **1** could be obtained in higher yield at much higher concentration of **1 u** by operating under an atmosphere of acetonitrile at 60 °C[¹³b] in the presence of 3 equiv. of DB24C8. In this way, pseudorotaxane **1** was isolated pure in a 82% yield after simple trituration in toluene.[²¹] Pleasingly, the N-succinimidyl carbonate extremity presented the advantage to be bulky enough to act as a pseudo stopper that slowed down the possible dethreading of the DB24C8, conferring kinetic stability on [2]pseudorotaxane **1**.[²²] Beyond the possibility to store **1** as a powder over time without degradation at room temperature, reactivity of the N-succinimidyl carbonate function towards nucleophiles such as amine compounds allowed for post-interlocking aminolysis of the thread's carbonate in mild conditions. This stopper exchange gave the opportunity to introduce a carbamate moiety in the threaded axle, as a potential secondary molecular station for the DB24C8. Reactions between pseudorotaxane **1** with either the dimethylbenzylamine or tetramethylxylylene diamine provided respectively the [2]rotaxane **2** and the palindromic[¹³a,²³] [3]rotaxane **4** (Scheme 1). Noteworthy, the mechanical bond

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Philip Waelès was born in Céret (France) in 1987. He obtained his B.Sc. at the university of Perpignan Via Domitia in 2010 and his M.Sc. in organic chemistry at the university of Montpellier (France) in 2012. He received his Ph.D. in 2016, from the same institution, by working on the synthesis of molecular muscles and lassos, under the supervision of Prof. Frédéric Coutrot. He is currently a CNRS Engineer in the Supramolecular Machines and ARchitectures Team of the Institut des Biomolécules Max Mousseron.

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Maxime Gauthier was born in Poitiers, France, in 1995. He received his B.Sc and M.Sc degrees in chemistry from the University of Montpellier in 2016 and 2018, respectively. He then joined the Supramolecular Machines and ARchitectures Team (SMART), headed by Prof. Frédéric Coutrot to carry out a Ph.D on rotaxane molecular machines. He obtained his PhD in 2021. His work focused on the influence of the surrounding macrocycle on the reactivity of a [2]rotaxane.

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Frédéric Coutrot was born in Paris, France, in 1973. He received his Ph.D. in 1999 from the university Henri Poincaré (Nancy, France). After being post-doc as a temporary lecturer for one year in the group of Dr. Michel Marraud (ENSIC, Nancy), he moved in 2000 to David Leigh's laboratory (UK) as a Marie-Curie Fellow for 2 years. In 2002, he was appointed assistant professor, then associate professor at the university of Montpellier, France. He is currently working on interlocked molecular machines as the head of the Supramolecular Machines and ARchitectures Team in the Institut des Biomolecules Max Mousseron.
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<figure><img src="image_14.png" /><figcaption>**Scheme 1.** a) previous work; b) current work: synthesis of the activated carbonate-containing pseudorotaxane 1, its post-synthetic modifications into [2]- and [3]rotaxanes, and the further *N*-chemical-responsive translational motion of the DB24C8 through deprotonation-then-*N*-carbamoylation of the ammonium moiety.</figcaption></figure>

was preserved because every reactional intermediate contained stoppers at both extremities of the encircled thread.

The translational motion of the DB24C8 was subsequently studied through the deprotonation-then-*N*-carbamoylation of the ammonium molecular station (Scheme 1, Figure 2 and Figure 3). This yielded the [2]rotaxane 3[24] and [3]rotaxane 5. Interestingly, the main accurate position of the DB24C8 around the carbamate station differed between **3** and **5**. The DB24C8 unsurprisingly interacted with the NH of the carbamate in both rotaxanes **3** and **5**. The DB24C8 also interacted with the *N*-side of the carbamate station in the [2]rotaxane **3**, while, unexpectedly, it only interacted with the *O*-side of the carbamate in the [3]rotaxane 5. This result highlighted the ability for a carbamate moiety to interact as a hydrogen bond donor through either one of the two sides of the carbamate function depending on its substituents. The different localizations of the DB24C8 in **3** and **5** were partly explained by the steric hindrance brought by the tetramethylxylyl moiety that hindered the region of the hydrogen-bond donors H₁₆, on the one hand, and to the

reciprocal steric repulsion between the two bulky DB24C8 in the case they were localized over the H₁₆ region. We should also mention that H₁₈ participated to the binding site in **3**. With respect to **3**, in **5**, the absence of such a hydrogen atom on carbon atom C₁₈ may therefore alter negatively the binding affinity of the *N*-side of the carbamate.

All these results that described the main *co*-conformational states of each [2]- and [3]rotaxane were evidenced by comparing the ¹H NMR spectra of [2]rotaxane species **2** and **3** with their non-interlocked thread analogues **2u** and **3u** (Figure 2), on one hand, and those of the [3]rotaxanes **4** and **5** with their non-interlocked thread analogues **4u** and **5u** on the other hand (Figure 3). At the initial protonated state, in **2** and **4**, the DB24C8 was localized around the best ammonium molecular station (Figure 2 a, Figure 2b and Figure 3a–b). Variations in the chemical shifts of hydrogen atoms between rotaxanes **2** or **4** and their respective non-interlocked threads **2u** or **4u** were very similar. The downfield shift observed for H₆ and H₈ in rotaxanes **2** and **4** (Δδ from 0.27 to 0.54 ppm) with respect to
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<figure><img src="image_16.png" /><figcaption>**Figure 2.** ¹H NMR (400 MHz, CD₃CN, 298 K) comparison between spectra of: (a) the protonated non-interlocked analogous molecular axle 2u; (b) the protonated [2]rotaxane 2; (c) the *N*-carbamoylated [2]rotaxane 3; (d) the *N*-carbamoylated non-interlocked analogous molecular axle 3u. The colour and numbering correspond to that indicated in scheme 1.</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 3.** ¹H NMR (400 MHz, CD₃CN, 298 K) comparison between spectra of: (a) the protonated non-interlocked analogous molecular axle 4u; (b) the protonated [3]rotaxane 4; (c) the *N*-carbamoylated [3]rotaxane 5; (d) the *N*-carbamoylated non-interlocked analogous molecular axle 5u. The colour and numbering correspond to that indicated in Scheme 1.</figcaption></figure>

their non-interlocked threads **2u** and **4u** highlighted their implication in hydrogen bonding with the lone pairs of the oxygen atoms of the DB24C8. Meanwhile, hydrogen atoms H₁ (Δδ *ca* -0.20 ppm), H₁₀⁻₁₂, (Δδ *ca* -0.23 ppm) and in a lesser extent H₉ and H₁₃ (Δδ from -0.10 to -0.14 ppm) all underwent upfield shifts in the rotaxane structures **2** and **4** due to their localizations in the shielding regions of the aromatic rings of the DB24C8.[25]

Deprotonation-then-*N*-carbamoylation of the ammonium moiety of [2]rotaxane **2** and [3]rotaxane **4** led to the displacement of the DB24C8 towards the carbamate station, this time with slight discrete localization on either sides of the carbamate station, as mentioned above. Figure 2c–d demonstrated the localization of the DB24C8 around the *N*-side of the carbamate moiety through the direct comparison between ¹H NMR spectra of **3u** and **3**. Indeed, in [2]rotaxane **3**, hydrogen atoms H₁₅, H₁₆ and H₁₈ were shifted downfield as a result of their ability to act as hydrogen bond donating groups with the lone pairs of the oxygen atoms of the DB24C8 (Δδ from 0.38 to 0.74 ppm). In the same time, hydrogen atoms H₁₀⁻₁₃, H₁₉ and H₂₁ were all shifted upfield because they experienced the shielding effect of the aromatic rings of the DB24C8 (Δδ from -0.12 to -0.29 ppm). In comparison, in [3]rotaxane **5**, the oxygen atoms of the two DB24C8 interacted through hydrogen bonds with the NH of the

carbamate (downfield shift Δδ=0.47 ppm for H₁₅) and with only the methylenic *O*-side of the carbamate, i. e. H₁₃ (downfield shift Δδ=0.39 ppm) (Scheme 1, Figure 3c–d). On contrary to what was observed in [2]rotaxane **3**, no variation of the chemical shift of H₁₆ was noticed in this case. Moreover, the part of the encircled thread that underwent the shielding effect of the aromatic rings of the DB24C8 concerned H₆, H₈⁻₁₁ and H₁₉ (Δδ from -0.07 to -0.25 ppm). These slight different localizations of the DB24C8 around the carbamate station were corroborated by the direct comparison between the ¹H NMR chemical shift of the hydrogen atoms H_E of the free DB24C8 and those of the surrounding DB24C8 in the respective rotaxanes **3** and **5** (Figures S3 and S6 of the SI). A higher shielding of the hydrogen atoms H_E was observed in **3** (with respect to H_E of the free DB24C8) than that observed in **5**. This correlates with a higher proximity between the crown ether and the shielding region of the aromatic ring of the *N*-benzylcarbamate moiety in **3**.

*Co*-conformational states of rotaxanes **3** and **5** were also confirmed by 2D-ROESY NMR experiments (see Figures S4 and S7 of SI). Indeed, in the [2]rotaxane **3**, ROE Correlation peaks between H<sub>C-E</sub> of the DB24C8 and the respective H<sub>16</sub> and H<sub>18</sub> of the *N*-side of the carbamate were noticed, while no correlation were present between H<sub>C-E</sub> and the *O*-side of the carbamate H<sub>13</sub>.
<figure><img src="image_18.png" /></figure>

The opposite was observed in the [3]rotaxane 5 – *i.e.* ROE correlation peaks between the O-side of the carbamate H₁₃ and H₉,₆ of the surrounding DB24C8 were noticed, while there were no correlation between the *N*-side of the carbamate H₁₆ and H₉,₅.

Noteworthy, the translational displacement of the DB24C8 could be inverted through Boc removal and subsequent anion exchange (Scheme 1).

## Conclusion

By the utilization of a stable though activated carbonate-containing pseudorotaxane, we have illustrated the possibility to obtain efficiently two-station [2]- and [3]rotaxanes thanks to a post-interlocking reaction that preserved the mechanical bond. Aminolysis of the carbonate function gave the opportunity to introduce a carbamate moiety in the backbone of the encircled molecular axle as a secondary molecular station for the DB24C8. Deprotonation-then-carbamoylation of the best ammonium station led to the translational motion of the DB24C8 along the threaded axle towards the carbamate station in both the [2]- and [3]rotaxanes, albeit with slight differences of localization depending on steric hindrance and electronic effect. Such a straightforward strategy, which is based on the post-synthetic transformation of a kinetically stable pseudorotaxane building block, may be of interest for the synthesis of more sophisticated molecular machines. This method appears particularly appealing and may save time for the challenging rotaxanation of molecular axles that are insoluble or fold in solvents that are required for the template-mediated reaction.

## Acknowledgements

We thank the "Agence Nationale de la Recherche" for funding MG under the project ANR-17-CE07-0014-01.

## Conflict of Interest

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** Carbamate • Mechanical bond • Rotaxanes • Supramolecular chemistry • Template

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[17] See Supporting Information for the synthesis of 1u.

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[19] See Supporting Information (section 7) for the ¹H NMR evidences relative to the formation of pseudorotaxane 1 over time.

[20] K. A. Connors, in *Chemical Kinetics: The Study of Reaction Rates in Solution*, 1990, p22, Wiley-VCH, Inc.

[21] Noteworthy, the DB24C8 and the non-interlocked thread **1u** were soluble enough in toluene to be removed, while pseudorotaxane **1** was not soluble in toluene.

[22] See Supporting Information (section 6.1) for all the ¹H NMR evidences of the pseudorotaxane structure 1.

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[24] ¹H NMR of the crude reaction indicated a complete conversion of rotaxane 2 into rotaxane 3 after one night. The low yield observed for the synthesis of compound 3 is attributed to loss of product during the purification by chromatography over silica gel.

[25] In Scheme 1, the main shape of the DB24C8 has been drawn as to illustrate the shielding effects underwent by the hydrogen atoms of the encircled thread.

Manuscript received: November 15, 2021

Revised manuscript received: February 10, 2022

Accepted manuscript online: February 11, 2022