Urea-Based [2]Rotaxanes as Effective Phase-Transfer Organocatalysts: Hydrogen-Bonding Cooperative Activation Enabled by the Mechanical Bond

We finely designed a set of [2]rotaxanes with urea threads and tested them as hydrogen-bonding phase-transfer catalysts in two different nucleophilic substitutions requiring the activation of the reactant fluoride anion. The [2]rotaxane bearing a fluorinated macrocycle and a fluorine-containing urea thread displayed significantly enhanced catalytic activity in comparison with the combination of both noninterlocked components. This fact highlights the notably beneficial role of the mechanical bond, cooperatively activating the processes through hydrogen-bonding interactions.

M echanically interlocked molecules (MIMs), 1 specially [2]rotaxanes, have emerged as promising ligands in metal-mediated catalysis and as organocatalysts. 2The unique orthogonal entwining of the two components enables tailored environments around the catalytic active sites. 3Additionally, the stabilizing effect of the macrocycle when placed over different functional groups at the thread, 4 coupled with the relative movement of the two components, makes rotaxanes ideal candidates for designing switchable catalysts 5 by facilitating both activation or deactivation of catalytic sites (ON/OFF) or the selection of different activation modes. 6ecent investigations have demonstrated that organocatalysts embedded in [2]rotaxane architectures with benzylic amidebased macrocycles show no decrease in their catalytic activity, but instead, the mechanical bond enhances the efficiency of the interlocked catalyst. 7ydrogen-bonding catalysis is a prevalent activation mode in homogeneous organocatalysis where small molecules with hydrogen bond donating groups, like diols, 8 (thio)ureas, 9 squaramides, 10 or guanidinium ions, are employed. 11This activation mode has also been recently incorporated into a few examples of rotaxanes acting as interlocked catalysts. 12nother well-known feature of hydrogen bond donors is their ability to interact with anions, thereby facilitating tasks such as recognition or anion-binding. 13Taking advantage of this property, Gouverneur and co-workers have recently reported an asymmetric fluorination process under hydrogenbonding phase-transfer catalysis (HB-PTC) using inorganic CsF as the nucleophilic fluoride source (Figure 1a). 14Their initial studies with monourea derivatives as catalysts indicated the convenience of activating the urea function with fluorinecontaining N-aryl groups to satisfactorily catalyze the process, whereas nonactivated ureas were found to be inactive because of their disability of transporting insoluble CsF into the organic solution.Inspired by that work, we designed a series of hydrogen-bonded rotaxanes 2 featuring a urea group at the thread serving as the hydrogen bond donor catalytic site.Additionally, we functionalized the isophthalamide fragments of the macrocycle with fluorine atoms in order to increase the acidity of its amide NH groups.This type of polyamide rings are well known to selectively recognize anions, often in a volume-selective manner, on the basis of their cavity size. 15onsequently, our designed systems incorporate two components, a macrocycle and thread, that could desirably shape an optimal environment for a cooperative interaction with the small fluoride anion, as shown in Figure 1b.As a result, the catalytic activity of the putative rotaxanes 2 under HB-PTC might be enhanced in comparison with the noninterlocked threads 1, and we hopefully expect a notable acceleration with the rotaxanes bearing activated fluorine-containing macrocycles.
For the synthesis of Leigh-type [2]rotaxanes, a suitable template on the thread is essential to facilitate the assembling of an entwined polyamide macrocycle via a five-component reaction with p-xylylenediamine and an isophthloyl dichloride. 16We selected the glycylglycine (GlyGly) as binding site, which was previously employed for this goal in hydrogenbonded rotaxane synthesis (Scheme 1). 17Reaction of the GlyGly-containing derivative 3 18 with 2,2-diphenylethyl isocyanate or 3,5-bis(trifluoromethyl)phenyl isocyanate yielded the urea-based threads 1a and 1b, respectively (see the Supporting Information for full synthetic procedures).Rotaxanes 2 were formed in reasonable yields by subjecting threads 1 to the standard conditions for hydrogen-bonded rotaxane formation using isophthaloyl chloride or perfluoroisophthaloyl dichloride, which has never been employed for this goal. 19The presence of fluorine atoms on the thread and macrocycle increases the acidity of the NH groups at both components of the rotaxanes.Computational calculations on the acidity of the amide groups within the macrocyclic rings were conducted using simplified models, which revealed a lower pK a for the amide groups in rotaxane 2c (pK a = 10.6) compared with rotaxane 2b (pK a = 15.0)(see Scheme S4). 20he diverse modifications at both threads and macrocycles, with the presence or absence of activating fluorine atoms, enable us to compare the catalytic capability of these systems and determine if, as we initially envisioned, the mechanical bond can cooperatively activate phase-transfer catalysis.
We next explored the catalytic activity of threads 1 and their respective rotaxanes 2 in the nucleophilic fluorination reaction of compounds 4 and 6 under HB-PTC with the aim to discern the impact of the mechanical bond on their respective performance (see optimization of the reaction conditions on Tables S1 and S2).By employing CsF as an insoluble inorganic fluoride source, no background reactions occurred (Table 1, entries 1 and 8). 23Threads 1a and 1b exhibited minimal activity in both reactions, which yielded low conversions of compounds 4 and 6 to the fluorinated products 5 and 7 (Table 1, entries 2 and 3; 9 and 10).Comparatively, the presence of the entwined fluorinated macrocycle in rotaxane 2a marginally enhanced its catalytic activity compared with the free thread 1a (Table 1, entries 2 and 4; 9 and 11).A similar trend was observed when comparing rotaxane 2b, featuring a nonfluorinated macrocycle, with its parent thread 1b, showing a slightly higher yield in the fluorinated derivative 5 by using as catalyst the interlocked species (Table 1, entries 3 and 5).Remarkably, rotaxane 2c comprising a fluorinated urea thread and a fluorinated macrocycle (for a total of 14 fluorine atoms) emerged as the most effective catalyst for both nucleophilic fluorinations to yield nearly quantitative yields of products 5 and 7 (Table 1, entries 6 and 12).As we expected, the mechanical bond, which linked both components, is crucial for the best catalytic performance of these systems.For the sake of further confirming the special role of the mechanical bond, we used an equimolecular mixture of free thread 1b and free fluorinated macrocycle (Mac) as the catalytic system, but such combination did not accelerate the nucleophilic fluorination (Table 1, entry 7).
Having in mind that both threads 1b and rotaxanes 2b,c similarly complex the fluoride anion present in solution (see titration data with TBAF in the Supporting Information), the enhanced catalytic activity showed by rotaxane 2c is mainly attributed to its capability to facilitate the transfer of the fluoride anion from solid CsF (insoluble in dichloromethane) into the solution.As we initially hypothesized, the fluorinated macrocycle in 2c featuring NH groups of high acidity likely participates in intramolecular hydrogen bonding with the oxygen of the urea moiety. 24This intramolecular interaction in 2c is evident at the solid state (Figure 2a) where one isophthalamide unit within the ring forms two bifurcated hydrogen bonds with the oxygen of the urea function.This cooperative interaction should enhance the affinity of the urea function toward the fluoride anion.Additionally, upon interaction with the fluoride anion, the second isophthalamide unit is available to establish additional hydrogen bonds with it.
In solution, analysis of the 1 H− 1 H NOESY spectrum of rotaxane 2c in the presence of 1 equiv of TBAF reveals intense cross peaks between some signals of the macrocycle (H F ) with others of the bis(trifluoromethyl)phenyl stopper (H g ), thereby indicating their spatial proximity once the 1:1 complex is formed (see Scheme 1 for lettering, Figures S22 and S23).This proximity is also observable in the 1 H− 19 F HOESY spectrum from which we find crosspeaks between the fluorine atoms at the macrocycle and the H g proton of the stopper (see Scheme 1 for lettering, Figures S24−27).Upon addition of increasing amount of TBAF, the macrocycle tends to be closer to the urea moiety for which we observe a deshielding of the signal attributed to the H b of the methylene group at the thread (see Scheme 1 for lettering, Figure S19).Computational simulations also revealed that the optimized structure of the 2c:F − (1:1) complex shows a cooperative bidentate binding mode in which 2c holds the fluoride atom involving the most acidic NH of the urea system (dF − •••H = 1.358Å, distance a in Figure 2b) and one NH of the isophthalamide moiety (dF 2b).Besides, one fluorine atom at the ortho position of one isophthalamide ring is directly interacting with the second NH of the urea fragment (dF•••H = 2.146 Å, distance c in Figure 2b), thus further enhancing the stability of the complex.Calculations also predict that the complexation energy of 2c:F − is higher than those of the other fluoride complexes tested (those with thread 1b and rotaxane 2b), which supports the conclusion that the capability of catalyst 2c to induce the phase transfer of the fluoride anion is the highest of the herein designed catalysts (see the Supporting Information).
In summary, we successfully synthesized a series of hydrogen-bonded interlocked urea derivatives and evaluated their efficacy as HB-PTC organocatalysts in two fluorination processes by using CsF as the nonsoluble nucleophilic fluoride source, and their reactivity was compared with their noninterlocked counterparts.As presumed, when the isophthalamide units of the macrocycle were substituted with electronwithdrawing fluorine atoms, the resulting rotaxane exhibited a spectacular improvement in its catalytic activity.These findings underscore the stark influence of the mechanical bond on the catalytic performance of these systems, which cooperatively activates the process by intercomponent hydrogen-bonding.Indeed, in the absence of the mechanical bond�more specifically by using the two segregated components of the rotaxane, the noninterlocked thread and macrocycle, as the catalytic system�the reaction did not occur.Our ongoing research aims to further explore the design of novel mechanical bonding phase-transfer catalysts, including their asymmetric variants, with the goal of enhancing the utility and versatility of mechanically interlocked catalysts.

* sı Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c06630.Supplemental experimental procedures, Figures S1−S30, Tables S1−S7, Cartesian coordinates of the computed structures and supplemental references (PDF) Accession Codes CCDC 2349096 and 2349097 contain the supplementary crystallographic data for this paper.These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Figure 1 .
Figure 1.(a) CsF nucleophilic fluorination process under hydrogen-bonding phase-transfer catalysis (HB-PTC). 14(b) Design of interlocked ureabased organocatalysts for HB-PTC with a cooperative activation by the mechanical bond (this work).Scheme 1. Synthesis of the Interlocked Systems 2 from Threads 1 a

Table 1 .
Evaluation of Threads 1 and Rotaxanes 2 in the HB-PTC with CsF a °C, 1200 rpm stirring; CsF used as provided by the supplier without any prior drying.b Determined by 19 F NMR using 4fluoroanisole as internal standard.c Reactions carried out with 5 mol % of catalyst for 10 h.