1 Introduction

Since Pedersen’s seminal report [1] of the synthesis and guest recognition behaviors of crown ether in the year of 1967, the research on host-guest recognition began to represent one of the major focuses in the field of supramolecular chemistry [2]. In the early stage, supramolecular chemistry was often referred to as host-guest chemistry [3], because of the following reasons. On the one hand, host molecules often exist in the form of macrocycles, which have many convergent binding sites that point into their cavities. The implication is that the host is able to accommodate a guest within its pocket where multiple noncovalent interactions could occur simultaneously in a cooperative manner. These supramolecular driving forces include labile coordination bond [4], π-electron interactions in the form of either donor-acceptor interactions [5] or aromatic radical-pairing interactions [6], solvophobic effect often in the form of hydrophobic forces [7] expressed in aqueous solutions, hydrogen bonding [8], electrostatic forces [9], anion binding [10], as well as a variety of van der Waals interactions [11]. On the other hand, host molecules often have preorganized conformations. As a consequence, host-guest recognition could occur without too much entropy loss in the cases when the guests have complementary sizes and geometries to fit within the host cavities. Host-guest recognition enables many tasks to be accomplished, including labile guest stabilization [12], accelerating reaction rates [13], as well as developing mechanically interlocked molecules [14].

Besides crown ethers, a few other macrocyclic molecules including cyclodextrins [15], calixarenes [16], cucurbiturils [17], and pillararenes [18] have been playing important roles in supramolecular chemistry. In the year of 1988, Sir Fraser Stoddart, the chemistry Nobel Laureate [19] of 2016 for his contribution in the development of molecular machines, designed and developed a rectangle-shaped host molecule, namely, cyclobis(paraquat-p-phenylene) (CBPQT4+) [20] (Fig. 1). This tetracationic cyclophane represents another milestone in the river of supramolecular chemistry, because (i) CBPQT4+ is relatively synthetically accessible and (ii) CBPQT4+ can recognize a variety of π-electron guests in both fully oxidized state and biscationic diradical state, driven by donor-acceptor and radical-pairing interactions, respectively.

Fig. 1
figure 1

Structural formula of the tetracationic cyclophane CBPQT4+ and its single-crystal X-ray structure. Counterions are omitted for the sake of clarity

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In this chapter, we are going to make a rough discussion of the following issues of CBPQT4+, including (i) the structural feature of CBPQT4+; (ii) its preparation including the template-directed synthesis; (iii) its binding behavior in its oxidized and radical states, namely, CBPQT4+ and CBPQT2(•+), respectively; (iv) mechanically interlocked molecules including rotaxanes and catenanes containing CBPQT4+ as a macrocyclic building block whose switchable features have been taken advantage of in the design of molecular switches and machines; and (v) the extended derivatives of CBPQT4+. Even although a few other groups also employed CBPQT4+ ring for self-assembly and molecular recognition, in this chapter, we mainly focus on the works of the group led by Stoddart, the inventor of this tetracationic cyclophane.

2 Structural Features

CBPQT4+ has been referred to as “Blue Box” in the community of supramolecular chemistry including the group of Sir Fraser Stoddart. Two major reasons might account for this “nickname.” First, the two 4,4′-bipyridinium (BIPY2+) units in CBPQT4+ can easily undergo reduction, producing blue-colored solution of CBPQT2(•+) containing two BIPY•+ moieties that absorb red wavelengths of light [21]. Second, the color of blue is often used to represent electron-deficient part in a molecule in the community of chemistry. The tetracationic CBPQT4+ ring has a π-electron-deficient nature. We therefore often employ blue color to draw the rectangular molecular structural formula of CBPQT4+, in order to indicate that this ring is electron-poor. This might be another origin of the name of “Blue Box.”

In the solid-state framework of CBPQT4+ [20] (Fig. 1), two BIPY2+ units are bridged in a face-to-face manner by two p-xylyl linkers. The rigidity of the building blocks, including both the BIPY2+ and the p-xylyl spacers, affords the cyclophane a preorganized and rigid cavity. The distance between the two BIPY2+ in their middle parts is around 6.8 Å, which is twice of π-π interaction distance. The implication is that, when a π-electron guest inserts into the macrocycle cavity, the interplane distances between the guest and each of the two BIPY2+ moieties would be around 3.4 Å, an optimized distance for the occurrence of π-π interactions. As a consequence, both of the two BIPY2+ units are able to undergo π-π interactions with the guest in the host cavity in a cooperative manner. This feature explains the phenomena that CBPQT4+ is highly promiscuous in binding a variety of π-electron-rich guests with complementary geometries.

It is also noteworthy that the BIPY2+ contains a few acidic protons, including the pyridinium protons in four α-positions with respect to the two pyridinium nitrogen atoms, as well as the methylene protons in the p-xylyl linkers. Their acidity results from the electron-withdrawing nature of the nitrogen atoms, on account of either conjugation or inductive effects. The consequence is that these protons represent promising hydrogen bond donors in host-guest recognition. More specifically, CBPQT4+ can provide larger binding affinities for those π-electron-rich guests that bear ethylene glycol side chains, whose oxygen atoms are considered hydrogen bond acceptors. This issue is discussed in more detail in the coming section.

The rectangle architecture of CBPQT4+ introduces ring strain. It is well-known that a sp3-hybridized carbon atom should have an optimized bond angle of around 109.5° in order to minimize the repulsion between the four bonding electron pairs. Considering each of the four methylene linkers in CBPQT4+ framework contains two less steric bulky protons, the optimized C–C–C bond angle (i.e., the central carbon is the methylene one) is supposed to be even larger than 109.5°. This value significantly deviates from 90° in a regular rectangle framework. This deviation indicates that in a CBPQT4+ framework, either the C–C–C bond angle is smaller than the optimized value, namely, 109.5°, or the BIPY2+ moiety or p-xylyl linker undergo bend. Both of these two behaviors introduce ring strain. In fact, in a solid-state structure of CBPQT4+, the C–C–C bond angle is observed to be around 108°. In addition, the two pyridinium moieties in a BIPY2+ are not in the same plane, which supports our aforementioned hypothesis that these aromatic building blocks in the CBPQT4+ framework have bent conformation.

The CBPQT4+ ring has an amphiphilic nature, i.e., its cationic BIPY2+ and the neutral p-xylyl building blocks are hydrophilic and hydrophobic, respectively. Therefore, the solubility of this tetracationic cyclophane is often determined by its counterions. When the counterions are less polar and hydrophobic PF6− or BF4−, the salts, namely, CBPQT4+•4PF6− or CBPQT4+•4BF4−, are soluble in polar organic solvents, such as MeCN, DMF, and MeNO2. When the counterions are changed to those that are highly solvated in water, including Cl−, Br−, or NO3−, the cyclophane becomes soluble in water.

3 Synthesis

The design of CBPQT4+ was based on the discovery [22] (Fig. 2) of the group led by Stoddart that a BIPY2+ derivative 12+ could be recognized by a crown ether containing two π-electron-rich hydroquinone (HQ) units, namely, bis-para-phenylene[34]crown-10 (BPP34C10). The driving forces for the formation of the complex 12+⊂BPP34C10 include charge-transfer interactions between the 12+ guest and the two HQ units in the host, which act as the π-electron acceptor and donor, respectively. The Stoddart research group thus envisioned that it might be possible to reverse the constitutionally roles of the host and guest, by introducing two BIPY2+ units into a macrocycle, namely, CBPQT4+, which was supposed to bind a π-electron-rich guest including a HQ derivative 2.

Fig. 2
figure 2

Structural formulaes and the corresponding single-crystal X-ray structures of BPP34C10 and CBPQT4+, before and after they recognize π-electron-deficient and rich guests 12+ and 2, respectively. Counterions are omitted for the sake of clarity

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The synthesis (Fig. 3) of CBPQT4+ relies on the SN2 reaction in which pyridine and benzyl bromide act as nucleophile and electrophile, respectively. The Stoddart group firstly synthesized compound 3•2PF6−, which has been referred to as “horseshoe” on account of its half-macrocyclic geometry. Combining 3•2PF6− and stoichiometric amount of α,α′-dibromo-p-xylene in dry polar organic solvent such as MeCN produced a yellow solid-state product including CBPQT4+ (counterion could be either Br− or PF6−), as well as other polymeric and oligomeric byproducts. Water has to be avoided during the reaction, because water might result in hydrolysis of benzyl bromide. By using chromatographic purification followed by counterion exchange, the Stoddart group obtained CBPQT4+•4PF6− in 12% yield, assuming that the salt was not solvated.

Fig. 3
figure 3

The non-template protocol for the synthesis of CBPQT4+•4PF6− by performing SN2 reaction of 32+•2PF6− and α,α′-dibromo-p-xylene in MeCN, followed by counterion exchange

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This 12% yield of CBPQT4+ is relatively low, compared with other [1+1] cyclization reactions. This low yield results from two major reasons. First, SN2 reaction is generally irreversible in most cases. The implication is that, if the reaction between 32+•2PF6− and α,α′-dibromo-p-xylene yields oligomeric or polymeric byproducts, the “errors” could not be corrected. Second, the ring stain of CBPQT4+ makes the cyclization less favored in the context of both thermodynamics and kinetics.

The effort to increase the yield of CBPQT4+ was performed [23] (Fig. 4) by using template-directed approach. The Stoddart group firstly prepared a guest 4 bearing a HQ moiety on which two ethylene glycol chains were grafted. The first SN2 reaction of 12+ and α,α′-dibromo-p-xylene yielded a triscationic reaction intermediate 53+. This π-electron-deficient pseudo-macrocycle “warp around” the guest 4, by which the terminal pyridine and benzyl bromide units orientated close to each other, favoring the occurrence of SN2 reaction in an intramolecular manner. In MeCN, the yield of CBPQT4+•4PF6− increased to 36% in the presence of 4, which is almost three times compared to that in the absence of template. It is noteworthy that when the solvent was switched from MeCN to DMF, the yield increased from 36% to 45%, which might be explained by the fact that the triscationic reaction intermediate 53+•2PF6–•Br− has better solubility in DMF. The same group also discovered that the yield of CBPQT4+ was dependent on the electron-donating ability of the guest. For example, when the guest 1,5-bis-[2-(2-methoxyethoxy)-ethoxy]naphthalene (BMEEN), an analogue of 4, was employed to template the formation of CBPQT4+ in DMF, the yield underwent further increase to 62%. This higher yield is attributed to the 1,5-dialkoxy-naphthalene (DNP) unit in BMEEN, which introduces stronger π-electron donor-acceptor interactions to the intermediate 53+, compared to the HQ unit in 4.

Fig. 4
figure 4

The template-directed protocol for the synthesis of CBPQT4+•4PF6− by performing SN2 reaction of 32+•2PF6− and α,α′-dibromo-p-xylene in the presence of a template 4 in MeCN, followed by guest removal and counterion exchange

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One of the disadvantages of using templates for the synthesis of CBPQT4+ is that template removal is technically demanding and time-consuming, especially in the case of high binding constant of guest⊂CBPQT4+. In fact, when the guest 1,5-bis[2-(2-hydroxyethoxy)ethoxy]-naphthalene (BHEEN) was employed to template the ring formation, it took a few days or weeks to remove the template from the ring cavity by performing liquid-liquid extraction. This problem was resolved (Fig. 5) by Stoddart group in the year 2010, by using a guest exchange strategy [24]. After the ring formation reaction, another guest 1,5-bis[2-(2-hydroxyethoxy)ethylamino]naphthalene (BHEAN), which contains a 1,5-diamino-naphthalene unit, was added into the aqueous solution of the reaction mixture to drive the template BHEEN out from the ring cavity, forming BHEAN⊂CBPQT4+. In the presence of acid, BHEAN undergoes protonation and exists in a cationic form, namely, BHEAN•2H+, thanks to the basicity of the amino functions in BHEAN. The cationic BHEAN•2H+ is no longer π-electron-rich and exhibits no binding affinity within the cavity of CBPQT4+. Adding NH4+•PF6− into the mixture in water could precipitate CBPQT4+•4PF6−, leaving the water-soluble BHEAN•2H+ in the aqueous solution.

Fig. 5
figure 5

The template-directed protocol for the synthesis of CBPQT4+•4PF6− by using BHEEN as the template. The guest removal is accomplished by means of guest exchange strategy. BHEAN is used to replace BHEEN in the ring cavity. In acidic condition, BHEAN is protonated and driven out from the ring cavity

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More recently, the Stoddart group developed [25] (Fig. 6) a pseudo-dynamic approach in the synthesis of CBPQT4+, as well as its extended derivative. Addition of tetrabutylammonium iodide into the ring closing reaction mixture of the 4,4′-bipyridine and a so-called reverse horseshoe compound 62+•2PF6− in refluxed MeCN could accelerate the reaction, producing CBPQT4+•4PF6− in 20% yield. The C–N bond formation is somewhat reversible, given that I− anion is both a good nucleophile and a good leaving group. This dynamic nature allows the system to perform error checking to some extent, producing more CBPQT4+, which is more thermodynamically favored in terms of entropy compared to those oligomeric byproducts.

Fig. 6
figure 6

The non-template protocol for the synthesis of CBPQT4+•4PF6− by performing SN2 reaction of 62+•2PF6− and 4,4′-bipyridine in MeCN in the presence of tetrabutylammonium iodide catalyst, followed by counterion exchange

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4 Guest Recognition Ability of CBPQT Ring

4.1 Guest Recognition Ability of CBPQT4+

As we mentioned before, CBPQT4+ is able to recognize a variety of π-electron-rich guests within its cavity. The driving forces for the host-guest recognition include:

  1. (i)

    π–π donor-acceptor interactions. This noncovalent force is also referred to as charge-transfer interactions. It is noteworthy that the width of CBPQT4+ ring, namely, 6.8 Å, allows the guest to be able to undergo π–π donor-acceptor interactions with both of the two BIPY2+ units in the host. However, in a given instant, only one of the two electron acceptors is strongly engaged in the noncovalent interactions. This proposition is supported by the observation that upon recognition of a π-electron-rich guest, the two BIPY2+ units in the CBPQT4+ ring have different reduction potentials on the cyclic voltammetry (CV) timescale, i.e., one BIPY2+ unit in the CBPQT4+ ring is easier to be reduced than the other one, in the cases when the dissociation process of the complex is slow or prohibited.

    Charge-transfer interactions lead to the optical absorption of the complexes in the visible light region, which brings about various colors of the complexes in solution. This is because when the complex absorbs a photon with a specific wavelength, electrons undergo transfer from the HOMO of the π-electron-rich guests to the LUMO of one of the two BIPY2+ units in the CBPQT4+ ring, leading a charge-separated excited state. For example, upon complexation with the CBPQT4+ ring, guest-bearing dioxyarene functions are typically orange to red [26], while diaminoarenes and TTF derivatives have green colors [27]. The difluorobenzidine-contained guest produces a blue color in solution [28].

    In addition, the difference in binding constants (Ka) for the guests bearing different π-electron moieties also reveals the occurrence and importance of π–π donor-acceptor interactions in guest recognition. For example, Ka of the guests containing a DNP unit are often a few order (two or three) of magnitude larger (Fig. 7) than that containing a HQ, on account of the fact that the former guest is generally more electron-rich than the latter. Tetrathiafulvalene (TTF), which is even more electron-donating than DNP, is used to synthesize guests with larger Ka. Introducing electron-withdrawing functional groups into the guest weakens the π–π donor-acceptor interactions and therefore reduces Ka. For example, the guest 4 bearing a HQ unit has a Ka of 2220 M−1 [26], which is nearly two order of magnitude larger than that of the analogue guest 7 bearing two fluorine atoms [29] (Fig. 8a). The guest 8 containing four fluorine atoms demonstrates no binding affinity.

    TTF undergoes reversible redox process. The oxidation products, including the monocationic TTF•+ and the dicationic TTF2+, are π-electron-deficient and therefore lose its ability to associate with the CBPQT4+ ring (Fig. 8b). This switching behavior was taken advantage of in the design of molecular switches and machines in the form of catenanes and rotaxanes. We will discuss it in more detail in the coming section.

  2. (ii)

    As we mentioned previously, the BIPY2+ in the CBPQT4+ ring contains a number of acidic protons that are considered as hydrogen bond donors. The implication is that, when the guest bears hydrogen bond acceptors such as glycol oxygen atoms, the host-guest recognition could be enhanced by hydrogen-bonding interactions in the form of [C–H•••O]. The occurrence of relatively strong hydrogen-bonding interactions for glycol chain relies on the gauche effect. That is, the two vicinal oxygen atoms in an ethylene glycol unit orientate in a manner that the O–C–C–O torsion angle is round 60°, instead of 180° that occurs in the case of C–C–C–C in a n-butane molecule. The gauche effect results from an orbital mixing between a C–H bond in a methylene and the empty anti-bonding orbital of the adjacent C–O bond. The gauche conformation of the glycol chain allows the glycol chain to wrap around a BIPY2+ unit, as a consequence of which, the multiple oxygen atoms in the former could form hydrogen bonds with one or a few acidic protons in a BIPY2+ unit simultaneously. This proposition is supported by the observation that when mono or di(ethylene glycol) chains are grated onto the guests bearing HQ or DNP moiety, Ka values of these guests to bind with CBPQT4+ could raise up by one or two orders of magnitude [26, 30] (Fig. 7).

  3. (iii)

    When some aromatic guests bearing HQ and DNP insert into the cavity of the host, the aromatic protons in the guests point toward one of the phenyl moieties in the p-xylyl linker of the host (Fig. 9). This orientation allows the occurrence of C–H•••π interaction, which, in some cases, act as the secondary driving force to strengthen the host-guest recognition. The occurrence of C–H•••π interaction could be convinced by the remarkable upfield shifts of the guest resonances in the corresponding 1H NMR spectra, given that the aromatic surfaces provide a shielded magnetic environment. Short contacts (e.g., 2.5 Å) between the protons in the guest and the phenyl moieties in the host also reveal its occurrence in solid state, as inferred from the single-crystal X-ray diffraction analysis.

  4. (iv)

    When the CBPQT4+ accommodates guest in water, in the case that the counterions were Cl−, Br−, or NO3−, hydrophobic effect might occur and enhance the host-guest recognition, even although hydrogen-bonding interactions are weakened in these cases. This hypothesis is supported by the stronger Ka for the macrocycle to accommodate the guest BHEEN in water than that in MeCN (see Fig. 7).

Fig. 7
figure 7

Association constants, Ka, of two series of pseudorotaxanes, in either MeCN or H2O. The guests contain either HQ or DNP units in the middle part

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Fig. 8
figure 8

(a) Association constants, Ka, of a series of pseudorotaxanes in MeCN. When more fluorine atoms are grafted onto the HQ in the guest, Ka undergoes significant decrease. (b) A pseudorotaxane TTF⊂CBPQT4+ undergoes dissociation after the TTF guest undergoes oxidation

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Fig. 9
figure 9

Structural formulaes and the corresponding single-crystal X-ray structures of two pseudorotaxanes. The guests contain either HQ or DNP units in the middle. C–H•••π interactions are clearly observed

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4.2 Guest Recognition Ability of CBPQT2(•+)

One of the reduced states of CBPQT4+, namely, the bisradical dicationic CBPQT2(•+), contains two BIPY•+ radical cations. Different from the BIPY2+ contains an empty LUMO that affords BIPY2+ the ability to function as a π-electron acceptor, the SOMO of a BIPY•+ already contains an electron. As a consequence, BIPY•+ is not capable of undergoing donor-acceptor interactions with π-electron donors. Instead, BIPY•+ undergoes a type of homo-loving interactions, namely, radical-pairing interactions [31]. That is, the two SOMOs of two BIPY•+ undergo efficient overlapping, forming a set of two larger delocalized molecular orbitals of a (BIPY•+)2 dimer. The two radical electrons thus occupy the newly formed HOMO of the (BIPY•+)2 dimer and therefore get spin paired. The formation of the diamagnetic (BIPY•+)2 dimer could be proven by the observation that a solution of BIPY•+ has clear EPR signal in the condition of low concentration and/or higher temperature, while in the condition of higher concentration and/or lower temperature, the EPR signal becomes weaker or even silent in some cases. The behavior that two identical aromatic radicals get spin paired by means of π-π stacking was also observed in a few of other aromatic radical systems, including TTF•+ radical cation [32] and naphthalene-1,8:4,5-bis(dicarboximide) (NDI•−) radical anion [33].

In the case of CBPQT2(•+), spin pairing does not occur to its two BIPY•+ units, because their distance, namely, 7 Å, is too large to allow the occurrence of radical spin pairing by means of π-π interactions, given that the efficient π-π interaction distance is around 3.5 Å. Instead, when a BIPY•+ guest inserts within the cavity, the guest is able to undergo spin-pairing interactions with both of the two BIPY•+ units in the macrocycle simultaneously, forming a BIPY•+⊂CBPQT2(•+) complex [21, 34] (Fig. 10). Because the formation of BIPY•+⊂CBPQT2(•+) is driven by the formation of “dual” (BIPY•+)2 dimers or a (BIPY•+)3 trimer, the binding constant Ka (i.e., 105 M−1) is generally significantly larger than that of the (BIPY•+)2 dimer.

Fig. 10
figure 10

Structural formulae and the corresponding single-crystal X-ray structures of BIPY•+ ⊂CBPQT2(•+). Counterions are omitted for the sake of clarity

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The formation of BIPY•+⊂CBPQT2(•+) has been convinced both experimentally and theoretically. The single-crystal X-ray diffraction analysis (Fig. 10) clearly demonstrates the formation of BIPY•+⊂CBPQT2(•+) in the solid state. In solution, the formation of BIPY•+⊂CBPQT2(•+) could be convinced by the following observations. First, the solution of BIPY•+⊂CBPQT2(•+) exhibits an absorption band in the near-IR (NIR) region in the UV-Vis-NIR absorption spectra, a characteristic absorption band indicating the formation of a (BIPY•+)2 dimer. This NIR absorption band is not observed in the solution of either BIPY•+ or CBPQT2(•+), ruling out the possibility of the occurrence of side-on dimerization of either (BIPY•+)2 or (CBPQT2(•+))2. Second, in the CV spectrum of a 1:1 mixture solution of BIPY•+ and CBPQT2(•+), BIPY•+ has a less negative reduction potential compared to that in its individual solution. This is because the formation of BIPY•+⊂CBPQT2(•+) acts as a driving force, making the reduction of BIPY2+ to BIPY•+ easier to occur.

The discovery of the complexation of BIPY•+⊂CBPQT2(•+) represents a milestone in the field of host-guest chemistry. First, radical-involved interactions begin to be employed as a driving force in host-guest recognition, even although for years radicals have been considered as labile species and infeasible to use in supramolecular recognition. Second, when this driving force is employed in the synthesis of mechanically interlocked molecules followed by oxidation, each of the latter molecules could contain a CBPQT4+ interlocked by a dumbbell or a ring containing a BIPY2+ unit. These interlocked components thus are repulsive to each other on account of Coulombic repulsion between these cationic building blocks, defying the commonly received viewpoint that mechanically interlocked molecules should contain mutually attractive components.

5 Mechanically Interlocked Molecules Containing CBPQT4+ Ring

Mechanically interlocked molecules (MIMs) [14a] have been considered as a type of nonclassic molecules. On the one hand, different from those normal or “classic” molecules whose atoms are all connected covalently with the molecular moiety, MIMs contain multiple components, between which covalent bonds are absent. When some noncovalent interactions occur between the interlocked molecular components, these MIMs might exist in some specific co-conformations. The preference of these co-conformations could be switched by using some external stimuli to tune these intercomponent intramolecular noncovalent interactions including either weakening the primary one or strengthening the secondary one, which results in mechanical movement of these molecular components with respect to each other. This behavior affords MIMs the ability to develop smart materials whose physical properties could be reversibly controlled. On the other hand, these molecular components are mechanically interlocked with each other, in reminiscence of the many interlocked rings in a necklace or metal chain. Without destroying at least one covalent bond, the architecture of a MIM would remain intact. This feature distinguishes MIMs from those supramolecular complexes, whose molecular components can undergo reversible association/dissociation.

The often studied MIMs include rotaxanes and catenanes, both of which contain a macrocyclic component that encircles either a dumbbell-shaped or another ring component, respectively. When a linear molecule is encircled by a ring, this system is called a pseudorotaxane, which is a type of supramolecular complexes. Pseudorotaxanes are often used as the precursors in the synthesis of rotaxanes and catenanes, when the terminal groups of the former undergo reactions with larger and bulky molecules, or each other, respectively. We are going to discuss it in more detail in the coming section.

5.1 Catenanes Containing CBPQT4+ Ring

The often used approach to obtain catenanes is the template-directed synthesis. Some noncovalent interactions are employed to drive a macrocycle to encircle a thread-shaped molecule, forming a so-called pseudorotaxane. The supramolecular driving forces are of importance, given that they lead to enthalpy release to compensate the entropy loss during the association of the supramolecular complex. When the two groups undergo reaction with each other or another molecule containing two reacting units simultaneously, which has been called “clipping,” a catenane is generated.

The formation of the donor-acceptor catenanes containing CBPQT4+ ring relies on the supramolecular interactions between a π-electron-rich ring and a CBPQT4+ ring. The driving forces include donor-acceptor interactions, hydrogen bonding, C–H•••π, as well as hydrophobic effect in aqueous solutions, as we mentioned before. The π-electron-rich ring thus often contains π-electron-rich unit such as DNP and TTF grafted with ethylene glycol chains. One approach to synthesize catenanes is by clipping a CBPQT4+ ring around a π-electron-rich unit in a crown ether template. That is, combining a π-electron-rich crown ether BPP34C10, α,α′-dibromo-p-xylene, and 32+•2PF6− in polar solvent, the latter two compounds would produce a CBPQT4+ ring around the π-electron-rich templating unit (Fig. 11) [35]. The overall yield of the catenane 94+•4PF6− was reported to be around 70%.

Fig. 11
figure 11

The template-directed synthesis for the synthesis of a catenane 94+•4PF6−

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It is also possible to clip the π-electron-rich ring around a BIPY2+ in a CBPQT4+ template. That is, a thread containing a central π-electron-rich unit bearing two ethylene glycol chains is recognized within the cavity of a CBPQT4+ ring. The two terminal groups undergo some high-yielding reactions, including Eglinton-Glaser-Hay coupling [36] (Fig. 12), Cooper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) [37], as well as esterification [38].

Fig. 12
figure 12

Synthesis of a series donor-acceptor [2]catenanes, by clipping via Eglinton-Glaser-Hay coupling

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A few reversible reactions were also employed in order to prepare the catenane in a reversible manner, such as imine bond formation [39], as well as metal-catalyzed olefin metathesis [40]. These dynamic approaches often resulted in higher yields, compared with those in the condition of irreversible ones. This is because (i) dynamic bond undergoes reversible forming/cleavage processes, which allows the systems to perform error checking, and therefore the MIMs are synthesized in a thermodynamic control and (ii) the guest recognition ability of CBPQT4+ acts as the driving forces, making the MIMs more thermodynamically favored compared with other byproducts.

Even although CBPQT4+ is considered as a macrocycle containing only irreversible covalent bonds, it has been discovered that one of the four C–N bonds between the pyridinium nitrogen and the methylene carbon could become reversible, by using iodide anion as both the nucleophile and leaving group. One of the methylene units in CBPQT4+ undergoes nucleophilic attack by an I− anion, forming a linear-shaped intermediate whose two terminal groups are benzyl iodide and pyridine, respectively. The driving force is the release of ring strain of the CBPQT4+ ring. In the presence of a π-electron-rich crown ether BPP34C10, the thread could be recognized within the cavity of the former, followed by an intramolecular SN2 reaction between the benzyl iodide and pyridine. The latter process recovers the ring and yields a catenane. The leaving group, namely, the I− anion, could undergo another attacking-followed-by-leaving cycle, catalyzing the transfer from CBPQT4+ to catenane 94+ [41] (Fig. 13).

Fig. 13
figure 13

Synthesis of a donor-acceptor [2]catenane 74+, by using a dynamic approach in which an I− anion acts as both the nucleophile that opens the CBPQT4+ ring and the leaving group that yields the catenane

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After the discovery of BIPY•+⊂CBPQT2(•+) complexation in reduction state, MIMs including catenanes containing CBPQT ring could be driven by radical-pairing interactions. In the year of 2013, Stoddart group reported (Fig. 14) the synthesis of a homo-catenane 108+, which is composed of two mechanically interlocked CBPQT ring [42]. A reverse horseshoe-shaped guest 62+ containing a central BIPY•+ moiety was recognized by a CBPQT2(•+), by using Zn dust to reduce the corresponding BIPY2+ units to radical states. The two benzyl bromide terminal groups in the former undergo SN2 reaction with the two pyridine functions in a 4,4′-bipyridine molecule simultaneously. After oxidation by using a strong oxidant, a catenane 108+ bearing eight positive charges could be obtained. Different from those donor-acceptor counterparts, this catenane contains two CBPQT4+ rings that are highly repulsively to each other, on account of the Coulombic repulsion between the cationic building blocks. This feature also brings about a unique property of this catenane. That is, in order to decrease the Coulombic repulsion, one or two of the BIPY2+ units in the catenane prefer to stay in the radical state, namely, BIPY•+. As a consequence, the radical is highly stabilized, opening up opportunities to develop purely organic paramagnetic materials.

Fig. 14
figure 14

Synthesis of a homo-[2]catenane 102+ composed of two mechanically interlocked CBPQT4+ ring by radical-pairing interactions. Counterions are omitted for the sake of clarity

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5.2 Rotaxanes Containing CBPQT4+ Ring

The donor-acceptor rotaxanes are obtained in a similar approach as their catenanes counterparts, relying on the ability of a CBPQT4+ ring or its precursors to recognize the π-electron-rich guests. Clipping reaction of α,α′-dibromo-p-xylene and 12+ occurs in the presence of a dumbbell, yielding the corresponding rotaxanes [43]. Because the C–H•••O hydrogen bonds play an even more important role than that of donor-acceptor interactions, it was observed that the dumbbells containing more ethylene glycol units often produced rotaxanes in higher yields. The threading-followed-by-stoppering strategy is also often used in the synthesis of rotaxanes containing a CBPQT4+ ring. Here the CBPQT4+ ring encircles a thread on its π-electron-rich binding station. The two terminal OH groups of the thread react with two larger bulky silicon derivatives whose volume should be larger than the cavity of CBPQT4+ ring to trap the corresponding rotaxane architectures [26] (Fig. 15). CuAAC [44], which has been referred to as click reaction, is an ideal reaction for rotaxanes synthesis [45], because of (i) high yield and (ii) room temperature condition that favors complexation.

Fig. 15
figure 15

Synthesis of rotaxanes by using a threading-followed-by-stoppering strategy. A 2,6-lutidine catalyzed Si–O bond formation is used for the stoppering reaction to capture the rotaxane structures

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The capability of CBPQT2(•+) to recognize a guest containing BIPY•+ was also taken advantage (Fig. 16) of by the Stoddart group in the synthesis of rotaxanes [46]. A complex 11•+⊂CBPQT2(•+) was self-assembled. Tris(2,2′-bipyridine)dichlororuthenium(II) was used as a sensitizer, which reduces the BIPY2+ units in both CBPQT4+ and 112+ to their radical states, in the presence of amino sacrificial reductant under visible light. The two azide terminal groups in 11•+ were introduced to undergo a type of click reaction, namely, azide-alkyne cycloaddition. An electron-deficient alkyne 12 was chosen, because it has a low-lying LUMO and therefore can undergo azide-alkyne cycloaddition without Cu(I) catalyst. Avoiding Cu(I) catalyst is of importance, due to its oxidative nature that might quench the BIPY•+ radicals. After the click reaction was accomplished, a rotaxane 136+ was obtained, whose dumbbell and ring components are repulsive to each other. A few years later, the Stoddart group also discovered [47] that the length of rotaxane could determine the stability of BIPY•+ radicals in the rotaxane against oxidation. In a shorter rotaxane, the distance between the CBPQT4+ ring and the central BIPY2+ unit in the dumbbell is smaller, which introduces larger Coulombic repulsion. The unfavorable repulsive interaction increases the tendency of the BIPY2+ unit to be reduced, as a consequence of which, the radical state of the short rotaxane is remarkably stabilized.

Fig. 16
figure 16

Synthesis of a rotaxane 136+ by using radical templation. The counterions are omitted for the sake of clarity

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6 Molecular Machines and Molecular Switches

As mentioned before, MIMs could be switched between different co-conformations by tuning the noncovalent interactions between the interlocked molecular components. First, these different co-conformers, whose covalent structures are essentially the same, might have dramatically different physical properties, such as color, luminescence, electric conductivity, hydrophilicity, as well as viscosity. This switching behavior could be used to design smart materials, whose properties could be controlled by employing external stimuli. For example, when a bistable rotaxane whose two co-conformers have remarkable difference in electric conductivity, it has the potential application in the design of molecular computer [48], i.e., the two co-conformers could represent “0” and “1,” respectively, for information storage. Second, switching between different co-conformers allows the components of a MIM to undergo intramolecular machinery mechanical movement, which could perform work on the surroundings and influence their properties. This potential ability opens up the opportunities for human to precisely control the microscopic world. The early trials include the nanoelectromechanical systems [49], in which the switching behavior of a MIM is employed to control the shapes and properties of an inorganic component. Using molecular switches to develop mechanized silica nanoscopic particles [50] for precisely targeted drug delivery represents another example of their potential applications.

In the year of 2016, the Nobel Prize in Chemistry was awarded to three chemists, including Jean-Pierre Sauvage [19a], Sir Fraser Stoddart [19b], as well as Bernard Feringa, on account of their contributions in the field of molecular machines. The former two chemists, namely, Jean-Pierre Sauvage and Sir Fraser Stoddart, employed MIMs in the design of molecular machines.

In order to shed light on the underneath mechanism how a molecular switch or machine works, we use a bistable rotaxane as a model compound. In the dumbbell component, two binding stations are introduced. This bistable rotaxane thus has two co-conformations, determined by which station the ring encircles. The ring is doing random Brownian movement along the dumbbell between the two stations, even although the energy barrier could be controllable by introducing a steric or electronic “speed bump” in the dumbbell between the two stations. When the macrocycle encircles the stronger or primary binding station, the rotaxane adopts a co-conformation that has been called ground state co-conformation (GSCC). In contrast, the co-conformation in which the ring sits on the weaker or secondary binding station has been called metastable-state co-conformation (MSCC). The ratio of the two co-conformations could be determined by the energy gap (ΔG) between the two co-conformations, as claimed by Boltzmann distribution, i.e., −ΔG = RTlnK (K is ratio of GSCC to MSCC). A molecular switch and machine based on a bistable catenane has a similar working mechanism, except that the dumbbell in a rotaxane is replaced by a macrocycle containing two binding stations in a catenane. When an external stimulus is introduced, which either weakens the binding between the primary binding station (i.e., station A) and the ring or strengthens the binding provided by the secondary binding station (i.e., station B), the preference of the macrocyclic component to encircle the two stations would change. That is, more macrocycles would prefer to encircle the station B, after addition of the external stimuli, which implies that it is a net effect that the ring is “moving” from station A to station B. This mechanism is different from its macroscopic counterparts, in which a macroscopic object undergoes direct change of its physical position. Removing the stimuli might recover the noncovalent bonding, and therefore the ring might move back to station A as a net effect.

In the year of 1994, the first molecular switch in the form of bistable [2]rotaxane 144+ containing CBPQT4+ as the macrocyclic component was synthesized [51] (Fig. 17) in the group led by Stoddart. The dumbbell component bears a benzidine as the primary station and a biphenol unit as the secondary one. The stronger binding affinity of benzidine compared to biphenol results from the fact that the two amino nitrogen atoms on benzidine represent better electron donors than the oxygen atoms on biphenol function. Either oxidation or protonation of the benzidine introduces a positive charge, which diminishes its binding affinity with the ring. As a consequence, the CBPQT4+ moves and encircles the biphenol station. Performing reduction or deprotonation of benzidine recovers its binding affinity, and therefore the ring moves back to this station.

Fig. 17
figure 17

The bistable [2]rotaxane 144+, which could be switched between two co-conformers by using redox or acid/base stimuli

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TTF, whose switching behavior under redox stimuli is more reversible than benzidine, was also employed in the design of molecular switches in the form of both multi-stable rotaxanes [52] and catenanes. For example, in the catenane 154+ (Fig. 18), TTF and DNP act as the primary and secondary binding station for the ring, respectively. The ratio of GSCC to MSCC is around 150:1 determined by using slow scan rate cyclic voltammetry [53], in which the ring encircles the TTF and DNP unit, respectively. Oxidation of TTF would drive the ring to reside on the DNP station [54]. When the secondary binding station is a di-alkyne linker that has no binding affinity with the CBPQT4+ ring, a so-called push-button molecular switch [36a] in the form of a catenane 164+ was obtained. That is, in the neutral state, the catenane 164+ adopts (Fig. 18) a co-conformation that the CBPQT4+ ring encircles the TTF unit almost exclusively, on account of the absence of any binding affinity between the di-alkyne linker and the CBPQT4+ ring. Upon oxidation of the TTF unit to its cationic forms, either TTF•+ or TTF2+, CBPQT4+ ring chooses to reside on the di-alkyne exclusively, in order to avoid Coulombic repulsion introduced by the cationic TTF•+ or TTF2+ unit.

Fig. 18
figure 18

The bistable [2]catenanes 154+ and 164+, in both of which, TTF acts as the primary binding station. In 154+, DNP acts as a secondary binding station. The ratio of GSCC to MSCC is around 150:1. Counterions are omitted for the sake of clarity

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This all-or-nothing switching behavior is even more obvious in the molecular switch whose switching behavior is driven by using the radical-pairing interactions. A bistable rotaxane 178+ was designed [21] (Fig. 19), containing a CBPQT4+ ring threaded onto a dumbbell that bears a DNP and a BIPY2+ unit. In the fully oxidized state, the tetracationic ring resides on the former station, driven by donor-acceptor interactions. The preference of the ring to encircle DNP is close to exclusive, given that DNP is the only π-electron-rich unit that has binding affinity with the ring. In the reduced state, the CBPQT2(•+) resides on the BIPY•+ station exclusively, driven by radical-pairing interactions. Introducing oxygen into the system could oxidize the radicals to the dicationic state, resetting the rotaxane. A few years later, the same group developed a light-stimulated “version,” namely, a bistable rotaxane 178+ [55] by introducing a photosensitizer as one of the two stoppers onto the rotaxane 178+. The light-stimulated excited state of a photosensitizer, namely, a tris(2,2′-bipyridine)dichlororuthenium(II) stopper, is able to reduce BIPY2+ units in the rotaxane into BIPY•+ in the presence of amino sacrificial reagent, namely, tri(ethanol)amine.

Fig. 19
figure 19

The light-stimulated bistable [2]catenanes 178+. In oxidative conditions, the ring encircles the DNP station. Under visible light, the tris(2,2′-bipyridine)dichlororuthenium(II) stopper can reduce the BIPY2+ units in both the ring and the dumbbell components with the assistance of N(CH2CH3)3 as a sacrificial reagent. After reduction, the ring shuttles and encircles the BIPY•+ station

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It is noteworthy that the aforementioned molecular switches produce the ring movement in a reciprocating manner. That is, when a stimulus is used to drive the movement of the CBPQT4+ ring, the work produced by the macrocycle would be cancelled or neutralized when we reset the molecular switch, because the ring returns to its original position by using a reversed pathway. Or expressed in another way, the net energy produced by the molecular switch is nothing after a full switching cycle. In order to produce a real artificial molecular machine that is able to produce useful work to the surroundings, a pseudorotaxane 18+⊂CBPQT4+ that produces unidirectional motion was designed [56] (Fig. 20). A CBPQT4+ ring encircles a DNP unit in a dumbbell-shaped molecule 18+ bearing two terminal units, namely, a neutral 2-isopropylphenyl group and a positively charged 3,5-dimethylpyridinium unit. The formation of the pseudorotaxane 18+⊂CBPQT4+ is again driven by donor-acceptor interactions. However, due to the Coulombic repulsion introduced by the 3,5-dimethylpyridinium, the association of the pseudorotaxane occurs in the manner that the ring passes the 2-isopropylphenyl unit. Reduction of the ring diminishes its binding affinity for the DNP station and therefore results in the dissociation of the pseudorotaxane. At the same time, the Coulombic repulsion between the reduced ring and the 3,5-dimethylpyridinium unit undergoes significant decrease. In order to avoid the steric hindrance introduced by the 2-isopropylphenyl group, the CBPQT2(•+) ring chooses to pass the 3,5-dimethylpyridinium unit to finish dissociation. These switching behaviors enable the ring to perform unidirectional movement from one end of the dumbbell to another, generating useful work.

Fig. 20
figure 20

A pseudorotaxane 18+⊂CBPQT4+ which can perform unidirectional association and dissociation motion under redox stimuli

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7 Extended Derivatives of CBPQT4+ Ring

A number of extended “versions” of CBPQT4+ rings were also designed and synthesized, which acts as larger counterparts of the small Blue Box. These extended derivatives are able to host either larger guests or in some cases, multiple guests simultaneously.

In the year of 1996, a wider counterpart of CBPQT4+ ring, namely, cyclobis(paraquat-4,4′-biphenylene) (CBPQB4+) [57], was obtained (Fig. 21), by using ferrocene, a relatively “thicker” guest to template its formation. The two BIPY2+ units are bridged by two 4,4′-bitolyl spacers, instead of the p-xylyl linkers in the synthesis of CBPQT4+. The distance between the two BIPY2+ units in CBPQB4+ is around 11 Å, enabling the ring to recognize two π-electron guests within the cavity, where both of the two guests undergo donor-acceptor interactions with the two BIPY2+ units in CBPQB4+ ring in an A-D-D-A manner (A, acceptor; D, donor). This recognition behavior opens up opportunities to use CBPQB4+ to synthesize [3]catenanes. In fact, the [3]catenane 204+ (Fig. 22) containing CBPQB4+ was even synthesized [58] before CBPQB4+ itself. The two crown ether rings in the 204+ act as the intrinsic templates for the ring closing reaction. A few years later, [3]catenane 214+ (Fig. 23) containing two TTF recognition sites was obtained [59]. Both the two TTF units in the two crown ether rings locate within the cavity of CBPQB4+. Interestingly, upon oxidation of TTF units into cationic TTF•+ radicals, the two TTF•+ units continue to reside within the macrocycle cavity, undergoing radical-pairing interactions. This behavior indicates that radical-pairing interactions within a (TTF•+)2 dimer are strong enough to overcome the Coulombic repulsion between the TTF•+ units and the tetracationic cyclophane. It is also strong enough to compensate the potential enthalpy release that results from the donor-acceptor interactions between the DNP unit and the CBPQB4+ ring. Further oxidizing TTF•+ to TTF2+ diminished the (TTF•+)2 radical-pairing interactions, leading to a co-conformation that the ring encircled the two DNP stations.

Fig. 21
figure 21

Structural formulaes of the extended derivatives of CBPQT4+

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Fig. 22
figure 22

Structural formula of a [3]catenane 204+

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Different from CBPQT2(•+) that can recognize a BIPY•+ guest, the ability of CBPQB2(•+) to accommodate two BIPY•+ guests in the cavity is relatively weak. This is probably because encapsulation of two BIPY•+ guests within the cavity of CBPQB2(•+) simultaneously leads to too much entropy loss. However, when the two BIPY•+ units are connected by two m-xylyl linkers, the macrocyclic 222(•+) could be recognized within the CBPQB2(•+) ring (Fig. 24a). The complex 222(•+)⊂CBPQB2(•+) [60] contains two (BIPY•+)2 dimers, as a consequence of which, it is diamagnetic and can be characterized by NMR spectroscopy. This ring-in-ring recognition is taken advantage of in synthesizing a rotaxane [61], whose dumbbell component contains a macrocyclic binding station.

In a recent report, by introducing an ethyne unit between the two phenyl rings in the 4,4′-bitolyl spacer, the Stoddart group obtained a wider cyclophane 194+. This ring in its radical state is able to accommodate a CBPQT2(•+), which, again, is driven by radical-pairing interactions. Within the cavity of 192(•+), the CBPQT2(•+) ring can still act as a host to recognize a variety of guests forming a series of supramolecular architectures that are reminiscence of the Russian dolls [62] (Fig. 24b).

The extension of CBPQT4+ could also be performed in the BIPY2+ part. By introducing a phenyl unit between the two pyridinium moieties in the BIPY•+ functions, a so-called Exbox4+ [63] was obtained. The central phenyl moiety is rather electron-deficient, due to the electron-withdrawing effect from the two pyridinium either by means of inductive effect or conjugation. Exbox4+ is thus able to recognize a few π-electron-rich aromatic hydrocarbon compounds, such as anthracene, phenanthrene, pyrene, etc.

Introducing two phenyl units in each of the two BIPY•+ functions in CBPQT4+ could produce an Ex2box4+ [64]. In the Ex2box4+, each of the central phenyl units is connected with only one of the two pyridinium units. The consequence is that the central biphenyl units do not have good π-electron-accepting ability. Instead, the cavity of Ex2box4+ has a dual feature. In the terminal part, the cavity is rather electron-poor and can recognize electron-rich guest, which is reminiscent of CBPQT4+ ring. In the middle part, the cavity of Ex2box4+ is able to recognize electron-deficient guest. Ex2box4+ is even able to accommodate two trichlorobenzene guests.

A few other extended boxes, including TVBox8+ [65], Ex2.2Box4+ [66], as well as ExBox24+ [67], were also synthesized, whose structures are illustrated in Fig. 21. In addition, now cage-shaped versions of CBPQT4+, namely, Excage6+ [68] and BlueCage6+ [69], were also obtained. These prism-shaped cages are composed of two triangular π-electron acceptors that are bridged by three spacers. Given that the triangular π-electron acceptors are triscationic and have better π-electron-accepting ability, these two cages often have larger binding affinity for π-electron-rich guests, compared to the ring counterparts (Figs. 23 and 24).

Fig. 23
figure 23

Structural formula of a [3]catenane 214+ and its redox-switching behavior

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Fig. 24
figure 24

Structural formulas of the ring-in-ring complexes, including (a) 222(•+)⊂CBPQB2(•+) and (b) Guest ⊂CBPQT2(•+)⊂192(•+)

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8 Conclusions and Outlook

In sum, the CBPQT4+ ring represents one of the most important macrocyclic hosts in the field of supramolecular chemistry and host-guest chemistry. It can recognize a variety of aromatic guests, most of which are π-electron-rich. These capabilities are based on (i) the rigid macrocycle framework of CBPQT4+, resulting in little to no entropy loss during guest accommodating, (ii) the distances between the two pyridinium moieties are optimal to allow the guests to undergo donor-acceptor interactions with both of them in either A-D-A or A-D-D-A manner. This host-guest recognition ability allows CBPQT4+ ring to be used as the building block to synthesize a variety of supramolecular or mechanically interlocked architectures.

The driving forces for CBPQT4+ to recognize guests including donor-acceptor interactions, hydrogen bonding, electrostatic forces, C–H•••π interaction, as well as hydrophobic effect are expressed in water. In the condition of reduction, the CBPQT2(•+) ring becomes attractive to BIPY•+ guests, driven by radical-pairing interactions. By tuning these driving forces, the host-guest complexation could be controlled, in the form of either dissociation of pseudorotaxanes or co-conformation switching in the case of bistable rotaxanes or catenanes. These switching behaviors of the CBPQT4+ ring based on supramolecular or mechanically interlocked architecture are taken advantage of in the design of molecular switches and machines, which could potentially be used in developing smart materials. The dream of human beings to precisely control the microscopic world might come true.

In order to allow the recognition of some larger guests, or realize multiple guest recognition, extended versions of CBPQT4+ ring were developed. These macrocycles demonstrate different guest recognition behavior from that of CBPQT4+ ring. Their recognition abilities enable more complex architectures to be synthesized.