Using Alkali Metal Ions To Template the Synthesis of Interlocked

Article Cite This: Acc. Chem. Res. 2018, 51, 1324−1337

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Using Alkali Metal Ions To Template the Synthesis of Interlocked Molecules Published as part of the Accounts of Chemical Research special issue “Supramolecular Chemistry in Confined Space and Organized Assemblies”. Alex Inthasot, Shun-Te Tung, and Sheng-Hsien Chiu*

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Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, Taiwan

CONSPECTUS: In 1987, Pedersen, Cram, and Lehn were awarded the Nobel Prize in Chemistry to honor their achievements in, among other things, the selective recognition of alkali metal ions by synthetic hosts. Almost three decades later, the 2016 Nobel Prize went to Stoddart, Sauvage, and Feringa for the development of artificial molecular machines, in which interlocked molecules play a significant role. Surprisingly, although many rotaxane- and catenane-based molecular machines have been constructed using various templating approaches, alkali metal ions, which are good templates for crown ether synthesis, have only rarely been applied as templates for the assembly of these interlocked molecules. This paucity of examples is probably due to the less well defined coordination numbers and geometries in the complexation of alkali metal ions to common oxygen-containing ligands, resulting in much weaker metal−ligand interactions and less predictable structures for their complexes compared with those formed between transition metal ions and common pyridine-containing ligands. Nevertheless, the ease of removing alkali metal ions from interlocked compounds and their much lower toxicity compared with that of transition metal ions are attractive features that have inspired their use as templates in the synthesis of interlocked molecules. About a decade ago, we began investigating the feasibility of using alkali metal ions to template the formation of catenanes and rotaxanes, with the hope of developing facile, broadly applicable, green, and efficient methods for their construction. We noticed that the interactions between oxygen-containing ligands and alkali metal ions can be strengthened by minimizing the effects of competing interactions from solvent molecules and counteranions. Thus, to increase the solubility of the metal ion salts in less polar solvents (e.g., CH2Cl2, CHCl3) and minimize ion pairing, we chose tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB), a weakly coordinating anion, as the counteranion for the alkali metal ions applied as templates. Our strategy has been based on the association of simple and general recognition units: (i) the orthogonal arrangement of two oligo(ethylene glycol) chains around an alkali metal ion and (ii) the encircling of a single urea/amide unit by an oligo(ethylene glycol)-containing macrocycle in the presence of a templating alkali metal ion. The former recognition system has allowed the facile construction of many interesting interlocked structures, including cyclic [2]catenane trimers and tetramers; the latter has provided several rotaxanes, including some incorporating monomers of practically important (macro)molecules (e.g., peptides, polymers) and some that behave as switches with unique functions (e.g., catalysis, gelation). The components in these recognition systems possess high flexibility in terms of their structures and the choice of suitable alkali metal ion templates. This Account tells the story of the concept behind this alkali metal ion-templating approach as well as its elaboration, scope, and recent advances. We hope to convince the reader that alkali metal ions are powerful templates for assembling interlocked structures and compounds and also to demonstrate the range of possibilities that they provide for future endeavors.

1. INTRODUCTION Since the earliest statistical preparations of catenanes and rotaxanes, interest in the syntheses and functions of these interlocked architectures has been ever-growing.1 They now find applications in a variety of fields (e.g., materials, drug © 2018 American Chemical Society

delivery, catalysis, molecular electronics), further motivating chemists to develop new methods for their construction.2 Received: February 12, 2018 Published: May 10, 2018 1324

DOI: 10.1021/acs.accounts.8b00071 Acc. Chem. Res. 2018, 51, 1324−1337

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Accounts of Chemical Research Scheme 1. Examples of Interlocked Compounds Capable of Binding Alkali Metal Ions

Scheme 2. Sanders’s Li+ Ion-Templated Formation of a Pseudorotaxane

their use as templates in the synthesis of interlocked molecules. Moreover, because the functionalities used in complexation to alkali metal ions are quite different from those generally applied in the chelation of transition metal ions, new doors have opened allowing the discovery of unique host/guest recognition pairs and novel functional interlocked switches. In this Account, we review some of our own efforts in using alkali metal ions as templates to assemble interlocked structures.

Template-directed synthesis has played a central role in the synthesis of interlocked molecules. Following Sauvage’s pioneering efforts preparing catenanes and rotaxanes,3 transition metal ions have become reliable and powerful templatesthey have well-defined coordination numbers and geometries and exhibit relatively strong chelation with nitrogencontaining ligands.4 A higher degree of sophistication has recently been achieved through “active metal template synthesis”, in which a transition metal ion not only serves as a template bringing the host and guest units together but also catalyzes the coupling of two guest ligands to interlock the components.5 Although strong metal−ligand interactions in transition metal ion-templated systems generally enhance the synthetic efficiency in the preparation of interlocked molecules, harsh conditions (e.g., KCN/heat) may be required to efficiently remove these metal ions from the final products.3 Complexation of alkali metal ions to common oxygen-containing ligands may suffer from weaker binding affinity and less well defined coordination numbers and geometries, but their much lower toxicity and ease of removal from interlocked compounds favor

2. INSPIRING LITERATURE PRECEDENTS 2.1. Complexation of Alkali Metal Ions to Interlocked Molecules

Unlike simple two-dimensional (2D) crown ethers, interlocked compounds have the potential to provide three-dimensional (3D) binding pockets for alkali metal ions; accordingly, examples of their use as alkali metal ion receptors and sensors have appeared. For example, Hiratani reported a fluorescent [1]rotaxane capable of detecting Li+ ions with an increased fluorescence intensity through a possible binding pocket formed from the oxygen atoms of ethylene glycol chains and 1325


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Accounts of Chemical Research

Scheme 3. Na+ Ion-Templated Formation of [2]Pseudorotaxanes from a Molecular Cage and Anthraquinone and Squaraine Guests and Their Solid-State Structures

Scheme 4. Sanders and Stoddart’s Li+ Ion-Controllable Neutral Molecular Switch

amide CO groups (Scheme 1a).6 In a similar manner, we reported a [2]rotaxane that binds some physiologically important metal ions (Li+, Na+, K+, Mg2+, Ca2+) within the binding pocket formed from a 2,2′-bipyridyl moiety and one of the di(ethylene glycol) loops of the interlocked macrocycle bis(p-xylyl)[26]crown-6 (BPX26C6) (Scheme 1b).7 Because each of the resulting metal complexes provided distinct signals in their respective 1H NMR spectra, the coinstantaneous identification of these metal ions in solution was possible merely by analyzing a single 1H NMR spectrum.

diimide (PMDI) moiety into the cavity of the host 1,5dinaphtho[38]crown-10 (1,5-DNP38C10) with the help of two Li+ ions (Scheme 2).8 We later reported the alkali metal ion-templated formation of [2]pseudorotaxanes from squaraine- and anthraquinone-based guests and a molecular cage as the host.9 The solid-state structures of these two types of [2]pseudorotaxanes (Scheme 3) revealed the chelation of the two CO oxygen atoms of the guest to the Na+ ions, which were themselves complexed to the [18]crown-6 (18C6) openings of the molecular cage. Because only the 18C6-complexed Na+ ions provided suitable chelating sitespointing into the cavities of the hostsfor the guests, the templating effect was highly selective for Na+ ions.

2.2. Alkali Metal Ion-Templated Formation of Pseudorotaxanes

Although the binding of alkali metal ions to interlocked compounds had been reported,6 examples of using alkali metal ions to efficiently arrange ligands into pseudorotaxane structures were relatively rare. In a pioneering example, Sanders described the threading of a guest featuring a pyromellitic

2.3. Use of Alkali Metal Ions To Operate Interlocked Switches

Stoddart and Sanders used Li+ ions to induce the reversible migration of an interlocked 1,5-DNP38C10 macrocycle 1326


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alkali metal ions as templates in the synthesis of catenanes and rotaxanes.

between the naphthalenediimide (NDI) and PMDI stations of the dumbbell-shaped component of a [2]rotaxane (Scheme 4).10 In the absence of Li+ ions, the interlocked macrocycle preferred to encircle the NDI station because of better stabilization through π−π stacking and C−H···O hydrogen bonds. The addition of Li+ ions to the solution led to migration of the macrocyclic component to the PMDI station, where the metal−ligand interactions were more energetically favorable and the resulting coordination pocket was much more suitable for the binding of Li+ ions. Furthermore, Leigh and Zerbetto constructed a molecular shuttle in which an interlocked 2,2′bipyridine-containing macrocycle selectively encircled a 4dimethylaminopyridine station in the presence of Li+ ions and an aniline station in their absence.11 Another [2]rotaxane, reported by us, had tertiary ammonium and urea stations installed in the threadlike component, allowing migration of an interlocked BPX26C6 component (Scheme 5).12 In the absence of metal ions, the macrocyclic

3. CATENANE SYNTHESIS 3.1. Concept

Similar to Sauvage’s classical catenane synthesis using Cu(I) ions to template the orthogonal alignment of two phenanthroline units, we found that Na+ ions are capable of directing the orthogonal alignment of two di(ethylene glycol) chains, thereby facilitating the synthesis of the corresponding [2]catenanes (Figure 1).13 Because the interactions between alkali metal ions and podands can be quite weak, care must be taken when choosing both the reaction solvent and the metal ion’s counteranion. To minimize the competing interactions of solvent molecules in chelating the alkali metal ions, the assembly must generally be performed in less polar solvents (e.g., CH2Cl2, CHCl3). To increase the solubility of metal ion salts in these solvents while minimizing ion pairing, the counteranions should be chosen as those that coordinate very weaklyfor example, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB).14 As outlined in Scheme 6, our reaction protocol for catenane synthesis involved dynamic imino bond formation between di(ethylene glycol)-containing diamine 1 and dialdehyde 2 in the presence of NaTFPB in CHCl3. In the presence of 0.5 equiv of NaTFPB, this mixture contained the [2]catenane [im3· Na][TFPB] as the predominant product at equilibrium. Using benzeneselenol (PhSeH) as the reducing agent, we converted [im3·Na]+ to [2]catenane 3 in an overall yield of 17% for the two steps. No extra reaction was needed to remove the complexed Na+ ions from the resulting [2]catenanesthey were lost during the workup and purification process. Because the [2]catenane [im3·Na][TFPB] was the predominant product observed in the 1H NMR spectrum of the reaction at equilibrium, we suspected that the low reaction yield (17%) was due to the lability of the imino bonds under the reduction conditions. Indeed, more efficient reduction of [im3·Na][TFPB] using NaBH4 gave [2]catenane 3 in 60% yield. The use of 1 equiv of Na+ ions for the same reaction led to preferential formation of the macrocycle [im4·Na][TFPB] at equilibrium, giving macrocycle 4 in 65% yield after the PhSeH-mediated reduction. The presence of Na+ ions was crucial for these reactions: no signals for the imino macrocycle im4 or the [2]catenane im3 were evident in 1H NMR spectra in the absence of Na+ ions. Because the binding pockets formed by the oligo(ethylene glycol) chains in common crown ethers and in [2]catenane 3 are quite different spatially (i.e., 2D planar and 3D orthogonal,

Scheme 5. A Na+ Ion-Controllable Molecular Switch

component resided at the tertiary ammonium station because of relatively strong hydrogen bonds; addition of Na+ ions to the solution, however, led to translocation of the macrocycle to the urea station as a result of coinstantaneous complexation of the Na+ ion to the urea and di(ethylene glycol) motifs of the guest and host components, respectively. When H2PO4 anions were added to remove the Na+ ions from solution by the formation of less soluble NaH2PO4, the interlocked BPX26C6 component migrated back to the tertiary ammonium station. These examples led us to surmise that alkali metal ions might be capable of templating the encircling of oligo(ethylene glycol)-containing macrocycles around simple functionalities such as oligo(ethylene glycol), urea, or amide units. Accordingly, we began investigating the possibility of using

Figure 1. Orthogonal alignment of (a) two phenanthroline units mediated by a Cu+ ion and (b) two di(ethylene glycol) units mediated by a Na+ ion and potential derivatization into a catenane. 1327


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Accounts of Chemical Research Scheme 6. Na+ Ion-Templated Synthesis of [2]Catenane 3 and Macrocycle 4

diamines bearing ethylene glycol chains of different lengths potentially requiring differently sized cations to selectively template the formation of their specific [2]catenanes. We conducted a systematic study of the reactions of dialdehyde 2 with a series of combinations of di-, tri-, and tetra(ethylene glycol)-containing diamines (1, 5, and 6, respectively) in the presence of various templating alkali metal ions.15 Although we could monitor the formation of the homo- and hetero[2]catenanes using 1H NMR spectroscopy, to confirm their formation we subjected the equilibrated mixtures to reduction (NaBH4) and methylation (HCHO/HCOOH) processes to allow isolation of the corresponding [2]catenanes (Scheme 7). We performed these Eschweiler−Clarke methylations to enhance the stability of the [2]catenanes under acidic conditions. As revealed in Scheme 7, Li+ and Na+ ions were the most efficient templates for the assembly of the di(ethylene glycol)containing homo[2]catenanes; the larger K+, Rb+, and Cs+ ions were incapable of promoting the synthesis of such small [2]catenanes. Similarly, the small Li+ ions could not template the formation of [2]catenanes from the diamines with tetra(ethylene glycol) motifs. These observations suggest the requirement for an appropriately sized binding pocket formed from the two orthogonally arranged oligo(ethylene glycol) chains and the cationic templates. Indeed, the relatively large Rb+ ions provided the highest efficiency in the assembly of tetra(ethylene glycol)-containing homo[2]catenanes, while K+ ions were the best choice for constructing tri(ethylene glycol)containing ones. When we applied diamines having ethylene glycol chains of two different lengths in the construction of hetero[2]catenanes, some homo[2]catenanes were also present as byproducts, with the selectivity depending on the size complementarity between the metal ion templates and the three possible binding pockets formed from the combination of the two different oligo(ethylene glycol) chains.

respectively), we investigated their different binding affinities toward alkali metal ions. We used isothermal titration calorimetry (ITC) to determine the association constants (Ka) for the interactions of the [2]catenane 3Me and its planar analogue 18C6 with Na+ ions in a mixture of CH2Cl2 and CH3CN (7:3), obtaining values of (3.8 ± 0.9) × 105 and (2.6 ± 0.8) × 106 M−1, respectively (Figure 2).15 Notably, although

3.3. Clipping of a Macrocyclic Guest

The ability to use alkali metal ions to template the selective assembly of hetero[2]catenanes from two interlocking imino macrocycles generated from two different oligo(ethylene glycol)-containing diamines and dialdehyde 2 implied that a particular imino macrocycle should be able to clip onto any macrocycle containing an oligo(ethylene glycol) moiety if the tendency to form homo[2]catenanes could be minimized. Because oligo(ethylene glycol) chains are frequently observed in the structures of many functional molecules, such a clipping method should allow them to be transformed into interlocked counterparts. We proved that such transformations are possible by reacting equimolar mixtures of diamine 1, dialdehyde 2, and NaTFPB with macrocycles 12 and 13 to afford, after reduction, the [2]catenanes 14 and 15 in yields of 28 and 21%, respectively (Scheme 8).16 Nevertheless, the selectivity was rather limited, with the homo[2]catenanes and their separate macrocycles also appearing in the reaction products.

Figure 2. Thermodynamic data for the binding of 3Me and 18C6 to Na+ ions.

the binding of [2]catenane 3Me with Na+ ions was weaker than that of 18C6, the interaction was enthalpically more favorable, suggesting that the disposition of two di(ethylene glycol) chains in an orthogonal alignment enhanced the binding to the cation. However, adopting such a 3D geometry to bind Na+ ions in the more sizable [2]catenane 3Me was entropically unfavorable, such that 18C6 became the better Na+ ion binder.

3.4. Cyclic [2]Catenane Oligomers

Although there have been great successes in making complicated interlocked and interwoven compounds, the covalent synthesis of cyclic [2]catenane trimers and tetramers has remained a challenge because their construction requires the correct processing of multiple macrocyclization reactions. Our alkali metal ion-directed synthesis of imino catenanes appeared to be a possible solution to the problemthe dynamic formation of imino bonds should allow correction of

3.2. Larger Homo- and Hetero[2]catenanes

Size-enlarged homo- and hetero[2]catenanes can be synthesized using the same alkali metal ion templating strategy, with 1328


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Scheme 7. Estimated Yields (from 1H NMR Spectra) of Selected Imino[2]Catenanes (Not Necessarily the Predominant Species) Assembled from Diamines 1, 5, and 6 and Dialdehyde 2 Using Different Alkali Metal Ions as Templatesa

Yields of reactions with no reliable signals identifying the [2]catenanes are denoted “−”. The numbers in parentheses are the isolated yields of the [2]catenanes after NaBH4-mediated reduction and Eschweiler−Clarke methylation.

a

Scheme 8. Na+ Ion-Templated Clipping Synthesis of [2]Catenanes 14 and 15 from Macrocycles 12 and 13

possibly mistaken linkages and lead to thermodynamically stable product(s). Thus, we applied tetraaldehyde 16, with two

perpendicularly aligned rigid dialdehyde arms presented from a carbazole core, as one of the reaction components (Scheme 9). 1329


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Accounts of Chemical Research Scheme 9. Self-Assembly Synthesis of Cyclic [2]Catenane Oligomers

around the di-, tri-, or tetra(ethylene glycol)-containing dumbbell-shaped guests 20−22, respectively, in the presence of templating Na+ ions in CHCl3.17 The corresponding [2]rotaxanes 23−25 were isolated in yields of 15, 20, and 8%, respectively, after reduction of the imino bonds. 4.1.2. Threading-Followed-by-Stoppering Approach. In addition to the clipping synthesis, alkali metal ions can direct the threading of an oligo(ethylene glycol) unit into the cavity of an oligo(ethylene glycol)-containing macrocycle, allowing the synthesis of a variety of rotaxanes through the so-called “threading-followed-by-stoppering” approach (Scheme 11a). Perhaps because an oligo(ethylene glycol) unit in a linear guest is less preorganized for binding to Na+ ions, resulting in weaker association of the components, the syntheses of these rotaxanes were better when performed under solvent-free conditions. Thus, [2]rotaxanes 30−32 were synthesized by grinding or ball-milling the concentrated residue from a CH2Cl2 solution of BPX26C6, the oligo(ethylene glycol)-containing threadlike molecule (26−28), and NaTFPB with isocyanate 29 in the presence of a catalytic amount of di-n-butyltin dilaurate (DBTDL) in yields ranging from 2 to 33%.18 The synthetic efficiency was related to the length of the oligo(ethylene glycol) chain, with tri(ethylene glycol) appearing to be the best choice [tetra(ethylene glycol), 2%; tri(ethylene glycol), 33%; di(ethylene glycol), 23%]. Such a preference may be explained by enthalpy/entropy compensation: tri(ethylene glycol) has more oxygen atoms than di(ethylene glycol) for complexation with a Na+ ion and is less flexible than tetra(ethylene glycol) when forming the threaded structure with the BPX26C6-complexed Na+ ion. We also performed a copper-free Huisgen cycloaddition under solvent-free conditions to synthesize [2]rotaxane 35

By reacting tetraaldehyde 16 (10 mM), diamine 1 (20 mM), and NaTFPB (10 mM) in CHCl2CHCl2, followed by reduction and methylation of the products, we isolated the cyclic [2]catenane dimer 17Me, the trimer 18Me, and the tetramer 19Me in yields of 5, 3, and 0.2%, respectively.17 The cyclic [2]catenane trimer 18Me and tetramer 19Me are the first examples of such stable covalent forms, arising from the reductions of multiple labile imino bonds in their precursors, themselves assembled directly from 12 and 16 independent components, respectively.

4. ROTAXANE SYNTHESIS Similar to the synthesis of catenanes, the alkali metal ion templating strategy can also be applied in the construction of a variety of rotaxanes. Here, in addition to the use of alkali metal ions to orthogonally align two oligo(ethylene glycol) chains, the same templates could also be used to direct the encircling of an oligo(ethylene glycol)-containing macrocycle around a urea or amide functionality in the rotaxane syntheses. The examples below demonstrate the synthetic flexibility in using these recognition systems to construct rotaxanes through both “clipping” and “threading-followed-by-stoppering” approaches. 4.1. Oligo(ethylene glycol)s as Guest Units

4.1.1. Clipping Approach. In section 3.3 we described how [2]catenanes can be formed through clipping of an imino macrocycle onto an oligo(ethylene glycol)-containing cyclic guest. It should not be too surprising to find that the same strategy can also be applied to synthesize rotaxanes through clipping of the same imino macrocycle onto a dumbbell-shaped linear guest featuring an oligo(ethylene glycol) motif. As displayed in Scheme 10, the macrocycle generated from the condensation of diamine 1 and dialdehyde 2 can be clipped 1330


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complexation of isocyanate 29 to the Na+-complexed BPX26C6.

Scheme 10. Clipping Synthesis of [2]Rotaxanes from Oligo(ethylene glycol)-Containing Dumbbell-Shaped Guests

4.2. Urea and Amide as Guest Units

4.2.1. Concept. In section 2.3, we noted that complexation to Na+ ions can lead to the migration of an interlocked BPX26C6 component from a tertiary ammonium station to a urea station in a molecular switch and that the same template could direct the threading of a linear oligo(ethylene glycol) chain into the cavity of BPX26C6. It therefore appeared that we might also be able to use a Na+ ion to template the threading of a urea- or amide-containing guest into the cavity of BPX26C6. As outlined in Scheme 12, we expected a guest featuring a urea Scheme 12. Possible Non-covalent Interactions Stabilizing a Urea-Containing Thread and Na+ Ion-Complexed BPX26C6 in the Form of a [2]Pseudorotaxane

Scheme 11. Na+ Ion-Templated Clipping Synthesis of [2]Rotaxanes Using Solvent-Free (a) Carbamation and (b) Huisgen Reactions

or amide functionality to be stabilized within the cavity of BPX26C6 not only through chelation of its CO group to a metal ion complexed to one of the macrocycle’s di(ethylene glycol) loops but also through hydrogen bonding of its NH proton(s) to the oxygen atoms of the other loop. However, possibly because of the high flexibility of the di(ethylene glycol) loops, we found that the association constant for the interaction of urea-containing guest 36 and Na+-complexed BPX26C6 (an infinite binding strength between these two species was assumed) in CDCl3 was only 176 ± 5 M−1 on the basis of 1 H NMR spectroscopic dilution experiments.19 4.2.2. Threading-Followed-by-Stoppering Approach. The alkali metal ion-templating recognition of oligo(ethylene glycol)-containing macrocyclic hosts to urea- or amidecontaining guests appeared to be highly flexible in terms of structure, allowing us to synthesize various rotaxanes from different hosts and guests to confirm the formation of their corresponding pseudorotaxanes in solution (Scheme 13).19 For instance, stoppering the pseudorotaxanes formed from BPX26C6, NaTFPB, and the urea-containing semidumbbells 37−39 (with their urea moieties conjugated to two, one, and zero aryl groups, respectively) through reactions with isocyanate 29 in CH2Cl2 afforded [2]rotaxanes 50, 55, and 56 in yields of 40, 25, and 8%, respectively. Likewise, the reactions of N−H conjugated (41) and nonconjugated (42, 43) amide-containing threadlike molecules with BPX26C6 and 29 in the presence of NaTFPB in CH2Cl2 led to the corresponding

from azide-terminated threadlike molecule 33 and alkyne 34 in 13% yield (Scheme 11b), eliminating any concerns that the successful syntheses of the [2]rotaxanes 30−32 were due to 1331


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Scheme 13. Rotaxanes Synthesized by Stoppering the Pseudorotaxanes Formed from Na+ Ion-Templated Threading of UreaAnd Amide-Containing Guests through the Cavities of Oligo(ethylene glycol)-Containing Macrocycles

metal ion templates were automatically removed from the [2]rotaxanes during the workup and purification processes. The higher efficiencies of the syntheses of the [2]rotaxanes when the guest urea or amide functionalities were conjugated to greater numbers of aryl groups can be rationalized by considering the higher acidity of their NH proton(s), leading to stronger hydrogen bonds with the encircling macrocycles (Scheme 12). Notably, similar reaction conditions did not allow the isolation of [2]rotaxanes from threadlike molecules containing ester functionalities, presumably because of the lack of NH units for hydrogen bonding and the weaker electron donation of an ester CO group for chelating a Na+ ion compared with those of amide and urea groups. Having determined that alkali metal ions can direct the threading of guests featuring only a single amide or urea

[2]rotaxanes 58−60 in yields of 73, 14, and 29%, respectively. Several different stoppering reactions were applied to interlock the components. For example, [2]rotaxane 61 was synthesized by using O-acylisourea stopper 47 to seal the [2]pseudorotaxane formed from threadlike molecule 43 and BPX26C6. KTFPB could also be used to template the synthesis of these rotaxanes, but, possibly because its larger size was not as complementary as a Na+ ion to the binding pocket, the yield of [2]rotaxane 60 synthesized using K+ ions as the template was relatively low (8%). The crucial role of the templating alkali metal ion in these recognition systems was further evidenced by the failure to isolate the product [2]rotaxanes under the same reaction conditions in the absence of the alkali metal ions. Similar to the situation in the catenane syntheses, the alkali 1332


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Accounts of Chemical Research Scheme 14. Na+ Ion-Templated Clipping Synthesis of [2]Rotaxane 73 and Its Solid-State Structure

Scheme 15. Na+ Ion-Templated Clipping Synthesis of [2]Rotaxanes from Various Dumbbell-Shaped Molecules

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Scheme 16. (a) Cartoon Representation of the Synthesis and Operating Concept of One-off Phototriggerable Gelation; (b, c) Synthesis and Selective Phototriggerable Gelation Behavior of Rotaxanes (b) 90 and (c) 91; (d) Practical Application of the Photopatterning Behavior of the Organogel

structures differ from BPX26C6 mainly in terms of variations in the di(ethylene glycol) loop, changing it to a 2,6-hydroxymethylpyridine (PBX26C6, PX25C7) or tri(ethylene glycol) (BX29C7) loop or a combination of the two (PBX29C7) or incorporating sulfur atoms (BX26S2C6). The successful syntheses of the corresponding [2]rotaxanes (yields: 8−43%) suggest that the recognition systems have quite a degree of flexibility in the structure of the host. Nevertheless, the efficiencies of the syntheses of the [2]rotaxanes relied on the stabilities of the [2]pseudorotaxanesthat is, they were strongly related to the size complementarity of the threadlike molecule, macrocycle, and template. Thus, the larger macrocycle BX29C7 gave relatively lower yields of products from the threadlike molecules 40 and 44 and required a bulkier stopper (49) for interlocking in the [2]rotaxanes 68 and 69, respectively. 4.2.4. Clipping Approach. To increase the practicality of introducing interlocked structures into (bio)molecules or polymers, it would be most useful to realize a “clipping” approach for the alkali metal ion-templated recognition systems because this would require no change in the structure of the guest species. Similar to the synthesis of the catenanes, we tested the idea of using a Na+ ion to direct the encircling of an

functionality through the cavity of the macrocycle, the ubiquity of these guest functionalities in many practical (macro)molecules suggested a simple method for using such recognition systems to introduce interlocked structures and/ or switching properties into many biorelated molecules (e.g., peptides) and artificial polymers (e.g., nylons). To demonstrate this concept, we mixed threadlike molecules having a nylon-6,6 repeating unit (45) or a triglycine residue (46) with BPX26C6 in the presence of NaTFPB, followed by reaction with 48 and 47, respectively, to give the corresponding [2]rotaxanes 65 and 66 in yields of 7 and 13%, respectively. In the synthesis of 66, we also isolated [3]rotaxane 67 in 8% yield, implying the possibility of using this strategy to prepare higher-order rotaxanes from long peptides. 4.2.3. Structural Flexibility. To investigate the flexibility in terms of the structure of the macrocycle threaded by urea- or amide-based guests through alkali metal ion templating, we tested five analogues of BPX26C6 (Scheme 13), namely, pyridobis(p-xylyl)[26]crown-6 (PBX26C6), pyrido-p-xylyl[25]crown-7 (PX25C7), bis(p-xylyl)[29]crown-7 (BX29C7), pyridobis(p-xylyl)[29]crown-7 (PBX29C7), and bis(p-xylyl)[26]dithia-crown-6 (BX26S2C6), for their complexation ability with various threadlike molecules (37, 39, 40, 43, 44).20 These 1334


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components about the two dumbbell-shaped gelators prevented them from aggregating and inhibited their gelation behavior in particular solvents. Because these macrocycles are photodegradable, UV (350 nm) irradiation of solutions of [2]rotaxanes 90 and 91 in dioxane and water, respectively, cleaved the macrocycles and released the free gelators into solution, resulting in gelation after the concentration of the free gelators reached the critical gelation concentration. Because the gelation was triggered by light, it could be controlled to occur only in those specific areas subjected to photoirradiation. We demonstrated this interesting property through selective gelation of part of a solution in an NMR tube and then took this process a step further to pattern a solution in a thin UV cell with the letters “NTU” (for “National Taiwan University”) through gelation of the nonmasked area under UV light. Thus, our alkali metal ion-templating strategy can be used not only to introduce one-off phototriggering gelation properties into known gelators but also to allow patternable gelation of solutions under UV light. This example illustrates how new properties and new applications of interlocked compounds are likely to result from the development of new recognition systems.

imino macrocycle, formed from a diamine and a dialdehyde, around the urea or amide functionality of a dumbbell-shaped guest. Reducing an equilibrated mixture of urea-containing dumbbell-like molecule 70, dialdehyde 71, diamine 72, and NaTFPB in CHCl3 (Scheme 14) gave the desired [2]rotaxane 73 in 11% yield along with the corresponding homo[2]catenane and its macrocycle as byproducts.21 We also synthesized eight other rotaxanes using two diamines (1, 72), four dumbbell-shaped molecules (74−77), dialdehyde 78, and Na+ ions (Scheme 15). Suitable choices of these reactants allowed us to increase the yields of the rotaxanes significantly for two reasons: (i) avoiding steric bulk around the urea/amide moiety favored the clipping reaction, and (ii) introducing hexyl groups into the diamine units improved the solubility of the related intermediates and products. Nevertheless, we found once again that the reaction efficiency correlated with the degree of aromatic conjugation of the amide and urea functionalities, with the same functionality having more directly linked aromatic rings affording higher yields of the corresponding rotaxanes. The threadlike molecule 74, with its urea unit linked directly to two aryl groups, gave its corresponding rotaxane 81 in a yield of 53%the highest for any of these clipping approaches. The same clipping reaction afforded only a 2% yield of the rotaxane when we applied the nonconjugated amide dumbbell 76 as the guest unit. Even though the reaction was not particularly efficient when the guests featured only one nonconjugated amide functionality, the efficiency improved greatly when the guest contained a few peptide-like repeating amide units. For example, we transformed the threadlike molecule 77, which contains two nonconjugated proximal amide units, to a [2]rotaxane in 36% yield. Notably, Li+ and K+ ions were not as good as Na+ ions in templating the clipping synthesis of [2]rotaxane 79; indeed, the yields of the imino precursor, determined using 1H NMR spectroscopy, were significantly lower (Li+, 72%; K+, 35%; Na+, 82%).

5.2. Activity-Controllable Catalyst

We have also used this recognition system and the clipping methodology to construct [2]rotaxane 92, which displays switchable activity in catalyzing the Michael addition between diethyl malonate and nitrostyrene (Scheme 17).23 One important feature of this [2]rotaxane is that its catalytic activity is correlated to control over the pirouetting motion of the interlocked macrocyclea less commonly examined phenomenon in contrast to most reported switchable rotaxane catalysts, in which the switching is based mainly on shuttling of the macrocyclic component.24 The conformation of [2]rotaxane 92 in its neutral state has the NH unit of the amide group hydrogen-bonded to the oxygen atoms of the tri(ethylene glycol) moiety of the macrocyclic component; it was catalytically inactive for the Michael addition reaction. The addition of Na+ ions, however, led to pirouetting of the macrocyclic component in relation to the amide guest, such that its tri(ethylene glycol) motif collaborated with the amide CO unit in complexation of the Na+ ion; this complex was catalytically active for the Michael addition. We believe that a plausible mechanism for the switching of the catalytic activity of [2]rotaxane 92 in the Michael addition involves the Na+ ioncomplexed state having a binding site available to coordinate the deprotonated diethyl malonate, allowing its reaction with the proximal nitrostyrene, itself activated through hydrogen bonding to the tertiary ammonium motif of the macrocyclic component. We managed to switch the activity of this [2]rotaxane-type catalyst in situ at least three times through the sequential addition of NaTFPB and [2.2.2]cryptand to introduce and remove the Na+ ions from the [2]rotaxane, respectively, as reflected coinstantaneously the observation of three “go” and “stop” cycles in the rate of the catalyzed Michael addition.

5. APPLICATIONS One of the purposes of developing new recognition systems for preparing new interlocked molecules or switches is to uncover unique functions that may lead to future practical applications. Indeed, we have found that rotaxanes constructed using this alkali metal ion-templating strategy can perform some interesting functions: sol−gel conversion and catalytic reactions. 5.1. Phototriggerable Gelators

As mentioned earlier, the ability to clip a macrocycle about a guest featuring a urea/amide unit should allow the construction of interlocked variants of many known functional molecules. The particular functions of the guests might be disturbed after interlocking with a macrocycle because of the greater steric bulk or possible shielding of the recognition functionality; this behavior provides an opportunity to deactivate and reactivate the functions of selective guests through the construction and destruction of their interlocked structures. We recently demonstrated this concept by developing two rotaxane-based phototriggerable gelators.22 Clipping the macrocycle generated from dialdehyde 78 and diamine 87 (bearing the photodegradable o-nitrobenzyl motif) onto the known amidecontaining organogelator 88 or the urea-containing hydrogelator 89 gave the [2]rotaxanes 90 and 91, respectively (Scheme 16). As expected, the encircling of the macrocyclic

6. CONCLUSION AND OUTLOOK In this Account, we have presented an overview of the use of alkali metal ions as templates for the construction of interlocked compounds. Because this recognition system targets guests having ubiquitous oligo(ethylene glycol), urea, and amide functionalities, these simple and flexible synthetic 1335


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Accounts of Chemical Research Scheme 17. (a) [2]Rotaxane 92 Displaying Na+ IonControllable Pirouetting Motion and Catalytic Activity; (b) Yields of the Michael Reaction Catalyzed by 92, Revealing Three “On”/“Off” Switching Cycles Controlled through the Sequential Addition of NaTFPB and [2.2.2]Cryptand

in Taiwan. His research work focused on the construction of complicated interlocked structures. Sheng-Hsien Chiu holds a B.S. in chemistry from National Taiwan University and a Ph.D. in supramolecular chemistry from the University of California at Los Angeles. He is now a Distinguished Professor at National Taiwan University. His research interests cover the development of new threading systems, the design of functional interlocked switches, and the assembly of complicated interlocked structures.

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approaches should facilitate the construction of a variety of new interlocked molecules from commonly accessible materials. We hope that our recognition systems will become useful new tools for the template-directed syntheses of many other interlocked molecules and that the resulting compounds will display interesting properties or functions that will realize the application of interlocked structures in our daily lives.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sheng-Hsien Chiu: 0000-0002-0040-1555 Notes

The authors declare no competing financial interest. Biographies Alex Inthasot obtained his Ph.D. in chemistry from a joint program between Université Libre de Bruxelles and Université Paris Descartes. He then worked as a postdoctoral researcher at National Taiwan University, where his research interests focused on the development of new interlocked systems controlled by light. Shun-Te Tung received his B.S. and Ph.D. in chemistry from National Taiwan University. He is now undertaking mandatory military service 1336


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Using Alkali Metal Ions To Template the Synthesis of Interlocked

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