Top Curr Chem (2014) DOI: 10.1007/128_2014_547 # Springer-Verlag Berlin Heidelberg 2014

Cyclodextrin-Based Molecular Machines Akihito Hashidzume, Hiroyasu Yamaguchi, and Akira Harada

Abstract This chapter overviews molecular machines based on cyclodextrins (CDs). The categories of CD-based molecular machines, external stimuli for CD-based molecular machines, and typical examples of CD-based molecular machines are briefly described. Keywords Catenanes
Cyclodextrins
Molecular machines
Pseudo-rotaxanes
Rotaxanes

Contents 1 Introduction 2 Categories of Cyclodextrin-Based Molecular Machines Based on the Structure and Mechanism 2.1 Rotaxanes and Pseudo-Rotaxanes 2.2 Catenanes 3 External Stimuli for Cyclodextrin-Based Molecular Machines [14] 3.1 Temperature 3.2 Pressure 3.3 pH 3.4 Chemicals 3.5 Light 3.6 Redox 4 Typical Examples of Cyclodextrin-Based Molecular Machines 4.1 Cyclodextrin-Based Molecular Switches 4.2 Cyclodextrin-Based Molecular Shuttles 4.3 Cyclodextrin-Based Molecular Rotational Motors 4.4 Cyclodextrin-Based Molecular Ratchets 4.5 Cyclodextrin-Based Molecular Knots 4.6 Cyclodextrin-Based Molecular Actuators A. Hashidzume, H. Yamaguchi, and A. Harada (*) Department of Macromolecular Science, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho, Toyonaka, Osaka 560-0043, Japan e-mail: [email protected]

A. Hashidzume et al. 4.7 Cyclodextrin-Based Molecular Sensors 4.8 Cyclodextrin-Based Molecular Printboards 4.9 Cyclodextrin-Based Controlled Release Systems 4.10 Cyclodextrin-Based Artificial Enzymes 5 Concluding Remarks References

Abbreviations 2D NMR AdCA CB[6] CD DMSO HPLC OEG PEG PGSE NMR ROESY STM TTF UV α-CD β-CD γ-CD λ τc

Two dimensional NMR 1-Adamantane carboxylic acid Cucurbit[6]uril Cyclodextrin Dimethyl sulfoxide High performance liquid chromatography Oligo(ethylene glycol) Poly(ethylene glycol) Pulsed field gradient spin-echo NMR Rotational Overhauser enhancement and exchange spectroscopy Scanning tunneling microscopy Tetrathiafulvalene Ultraviolet α-Cyclodextrin β-Cyclodextrin γ-Cyclodextrin Wavelength Rotational correlation time

1 Introduction A machine is defined as “an apparatus using mechanical power and having several parts, each with a definite function and together performing a particular task.” When the word “parts” is replaced with “molecules,” a machine turns into a molecular machine. Thus, a molecular machine can be defined as an assembly of a distinct number of molecules designed to perform machine-like movements in response to external stimuli. In biological systems, various types of molecular machines composed of macromolecules, e.g., nucleic acids and proteins, drive a wide variety of chemical reactions necessary for living activities, e.g., contractionexpansion movement of muscle fibers, exclusion of foreign materials by white blood cells and antibodies, enzymatic reactions, and transportation of molecular oxygen and nutrients. Hence, biological molecular machines have been inspiring a number of research groups in supramolecular chemistry to devote their effort to fabrication of artificial molecular machines (see other chapters in this book).

Cyclodextrin-Based Molecular Machines Table 1 Basic characteristics of CDs [1]

Number of glucose units Molecular weight Cavity diameter (Å) Height (Å)

6 972 4.7–5.3 7.9  1

7 1,135 6.0–6.5 7.9  1

8 1,297 7.5–8.3 7.9  1

Cyclodextrins (CDs) are cyclic oligomers of D-(+)-glucopyranose units linked through an α-1,4-glycoside bond. CDs of 6, 7, and 8 glucopyranose units are called α-CD, β-CD, and γ-CD, respectively (Table 1). CDs are toroidal with narrower primary hydroxyl and wider secondary hydroxyl sides. Since CDs possess their hydrophilic exterior and hydrophobic cavity, CDs interact selectively with hydrophobic compounds of size and shape matching their cavity to form inclusion complexes in aqueous media. On the basis of this phenomenon, CDs have been widely used as an important building block of supramolecular architecture [2–6]. Various examples of molecular machines based on CDs have also been reported to date [7–10]. This chapter overviews molecular machines based on CDs. In Sect. 2, CD-based molecular machines are categorized based on the structure and mechanism. Section 3 briefly describes external stimuli for CD-based molecular machines. Section 4 deals with typical examples of CD-based molecular machines.

2 Categories of Cyclodextrin-Based Molecular Machines Based on the Structure and Mechanism CD-based molecular machines can be categorized into (1) rotaxanes and pseudorotaxanes and (2) catenanes. They can be further divided into subcategories based on their mechanism, as can be seen in Fig. 1.

2.1

Rotaxanes and Pseudo-Rotaxanes

CD-based molecular machines of rotaxanes and pseudo-rotaxanes can operate using (1) inclusion and dissociation (Fig. 1a), (2) translation (Fig. 1b), and/or (3) rotation (Fig. 1c).

A. Hashidzume et al. Fig. 1 Categories of CD-based molecular machines based on the structure and mechanism: inclusion and dissociation of pseudo-rotaxane (a), translation of the rotor along the axis in (pseudo-) rotaxane (b), rotation of the rotor around the axis in (pseudo-)rotaxane (c), translation of the rotor along the macrocycle in catenane (d), and rotation of the rotor along the macrocycle in catenane (e)

Inclusion and dissociation are the essential behavior of inclusion complexes of CDs. A number of examples of molecular machines based on inclusion and dissociation have been reported so far, presumably because of ease of synthesis. This type of CD-based molecular machines can be applied to various functions, including molecular switches, molecular actuators, molecular knots, molecular sensors, molecular ratchets, molecular printboards, molecular controlled release systems, and artificial enzymes. The CD rotor in rotaxanes or pseudo-rotaxanes can translate on the axis if the axis is long enough. The translation of the CD rotor in rotaxanes and pseudorotaxanes has also been widely utilized for molecular machines because various types of axis molecules can be synthesized and employed. This type of CD-based molecular machine has been reported as molecular shuttles, molecular actuators, and molecular knots. The CD rotor in rotaxanes or pseudo-rotaxanes can rotate around the axis because of the low rotational barrier. The rotation of the CD rotor around the axis in rotaxanes and pseudo-rotaxanes can also be used in molecular machines, but it is still difficult to detect the rotation of CD rotors, presumably because of the rotationally-symmetrical structure and fast rotation of CD. This type of CD-based molecular machine can be applied to molecular rotational motors and molecular ratchets.

Cyclodextrin-Based Molecular Machines

2.2

Catenanes

CD-based molecular machines of catenanes can operate using (1) translation (Fig. 1d) and/or (2) rotation of the CD moiety (Fig. 1e). The CD moiety in catenanes can also translate along the other macrocycle when the macrocycle is large enough. The translation of the CD moiety in catenanes can be monitored if the other macrocycle contains spectroscopically-active moieties, e.g., chromophores and fluorophores. This type of CD-based molecular machines can be utilized as molecular rotational motors and molecular switches. The CD moiety in catenanes can rotate around part of the other macrocycle axis when the macrocycle is large enough. The rotation of the CD moiety can also be applied to molecular motors and molecular switches. Only a few examples of CD-based catenanes have been reported [11–13].

3 External Stimuli for Cyclodextrin-Based Molecular Machines [14] Molecular machines are often a class of supramolecular assemblies responsive to external stimuli. External stimuli, which can cause operation of CD-based molecular machines, include temperature, pressure, pH, chemicals, light, and redox.

3.1

Temperature

Temperature is the most common external stimulus for stimuli-responsive supramolecular assemblies. Since the inclusion behavior of CDs is usually enthalpicallydriven, CDs include guest compounds to form inclusion complexes at lower temperatures whereas the inclusion complexes are dissociated at higher temperatures.

3.2

Pressure

Pressure is a common stimulus for stimuli-responsive supramolecular assemblies. Since sonic and ultrasonic waves, which are oscillations of pressure, can vibrate and stress materials, these waves can also be utilized as a stimulus for molecular machines. However, there have been only a few examples of CD-based molecular machines controlled by pressure, presumably because of experimental difficulties in applying pressure [15].

A. Hashidzume et al.

3.3

pH

pH is another popular external stimulus for stimuli-responsive supramolecular assemblies. As the pH of the medium is varied, weak acids and bases are converted from their acidic forms to their basic forms or vice versa around their pKa or pKb, respectively. It is known that CDs do not interact significantly with cationic species. Thus, CDs form inclusion complexes with weak bases, e.g., amines and pyridines, at higher pH, whereas the inclusion complexes are dissociated at lower pH.

3.4

Chemicals

Chemicals are another popular class of external stimuli for stimuli-responsive supramolecular assemblies. Chemical stimuli can be categorized as competitors for binding sites or modifiers of the medium quality. As described in the introduction part, CDs include selectively hydrophobic guest compounds of size and shape matching the cavity in aqueous media. When a competitive guest or host is added to inclusion complexes, the equilibrium is shifted, i.e., some of the initial inclusion complexes are dissociated and inclusion complexes with the competitor added are formed, depending on the concentration and binding constant. When an organic compound, which is miscible with water, is added to the aqueous solution of inclusion complexes, the guest compounds may become more solvophilic, resulting in dissociation of the inclusion complexes.

3.5

Light

Light, i.e., the electromagnetic wave, is an external stimulus, which has been widely applied in stimuli-responsive supramolecular assemblies recently. The energy of light varies over a wide range, depending on the wavelength (λ). Since near ultraviolet (UV) or visible light (λ ¼ 200–750 nm) can electronically excite chromophores leading to their structural change, near-UV or visible light is usually used as a stimulus for supramolecular assemblies. Photoinduced structural changes include photoisomerization, photodimerization, and photoinduced decomposition. Popular photo-responsive guests for CDs are azobenzene and stilbene, which undergo trans-to-cis (or E-to-Z ) and cis-to-trans (or Z-to-E) photoisomerization. The trans isomer is included strongly by α-CD, but the cis isomer is not [16, 17]. It should be noted that trans-azobenzene preferentially includes α-CD whereas the cis isomer preferentially includes β-CD [18, 19].

Cyclodextrin-Based Molecular Machines

3.6

Redox

Redox is a promising stimulus for supramolecular assemblies because the redox state can be switched chemically or electrochemically. When a material undergoes redox reactions, the electronic state is switched. Redox-responsive residues contain metal complexes (e.g., metalocenes and porphyrins), aromatic moieties, disulfides, peroxides, etc., which act as electron acceptors or donors. Popular redox-responsive guests for CDs are metallocenes [20–24]. Ferrocene, i.e., the reduced state, is included rather strongly by β-CD, whereas ferrocenium, i.e., the oxidized state, is not included because of its positive charge.

4 Typical Examples of Cyclodextrin-Based Molecular Machines 4.1

Cyclodextrin-Based Molecular Switches

Inclusion complexes, which change their structures in response to external stimuli, can be used as molecular switches. A number of molecular switches, i.e., stimuliresponsive inclusion complexes, have been reported [10]. A β-CD modified with a pyridin-4-yl indolizin moiety on the 6-position through an amide linkage was reported as a pH-driven molecular switch (Scheme 1) [25]. The modified β-CD emits fluorescence efficiently at neutral pH, whereas it does not at acidic pH (~3). This is because the fluorophore moiety is included by the β-CD cavity under the neutral conditions, but it is protonated and exists outside the β-CD cavity under the acidic conditions. A combination of β-CD, cucurbrit[6]uril (CB[6]), 1-adamantanylhexylamine, and 1-adamantanyldimethylhexylammonium iodide was reported as a pH-driven four-component molecular switch (Scheme 2) [26]. At basic pH, β-CD and CB[6] include 1-adamantanylhexylamine and 1-adamantanyldimethylhexylammonium iodide, respectively. This is because β-CD and CB[6] include preferably neutral and cationic species, respectively. At neutral or acidic pH, on the other hand, these host molecules switch partners: β-CD and CB [6] include favorably 1-adamantanyldimethylhexylammonium iodide and 1-adamantanylhexylammonium chloride, respectively, because of hydrogen bond formation between the ammonium NH and carbonyl groups in CB[6]. Another pH-driven molecular switch was reported based on a cationic axis molecule, 1,10 -decane-1,10-diyldipyridinium dibromide, and α-CD derivatives modified with a pyridine or amine moiety [27]. The α-CD derivatives include the axis molecule under neutral conditions, whereas a significant fraction of the inclusion complexes are dissociated under acidic conditions because of the electrostatic repulsion (Scheme 3).

A. Hashidzume et al.

Scheme 1 A pH-driven cyclodextrin-based molecular switch

Scheme 2 A pH-driven four-component molecular switch

Scheme 3 A pH-driven cyclodextrin-based molecular switch

A photo-driven molecular switch was reported based on a simple ternary mixture of β-CD, 1-bromonaphthalene, and an Alizarine Yellow R derivative (sodium 2-methoxy-5-((4-nitrophenyl)diazenyl)benzoate) (Scheme 4) [28]. In the trans state of the Alizarine Yellow R, β-CD includes the azo chromophore. Under irradiation at 360 nm, the Alizarine Yellow R is isomerized from trans to cis, resulting in dissociation of the inclusion complex of β-CD with the azo chromophore. Thus, β-CD includes 1-bromonaphthalene preferably, and the 1-bromonaphthalene emits

Cyclodextrin-Based Molecular Machines

Scheme 4 A photo-driven cyclodextrin-based molecular switch

Fig. 2 Photo-responsive interconversion between supramolecular cyclic dimer and oligomer

strong phosphorescence in the complexed state even at room temperature. Under irradiation at 430 nm, the Alizarine Yellow R is isomerized from cis to trans and the trans isomer ejects 1-bromonaphthalene, leading to turning off the room temperature phosphorescence. CDs modified with a stilbene or azobenzene moiety can form supramolecular oligomers and polymers depending on the structure, which may switch their supramolecular structures in response to light. A combination of a β-CD dimer linked through a 4,40 -stilbene moiety and an adamantane dimer linked through a 4,40 -trimethylene dipyridinium moiety forms a supramolecular cyclic dimer in the trans state of the stilbene moiety. Under irradiation at 350 nm, the stilbene moiety in the β-CD dimer is isomerized from trans to cis, and the β-CD dimer and adamantane dimer form supramolecular oligomers presumably because of a steric effect. Under irradiation at 254 nm, the stilbene moiety is isomerized back to trans, and the dimers thus form a supramolecular cyclic dimer (Fig. 2) [29]. An α-CD derivative modified with a stilbene moiety on the 3-position through an amide linkage forms a stable doubly-threaded dimer in the trans state of the stilbene moiety. Whereas the α-CD derivative forms supramolecular assemblies in its cis state after irradiation at 340 nm. The characterization data obtained by NMR, mass,

A. Hashidzume et al. Fig. 3 Photo-responsive interconversion between doubly-threaded dimer and aggregate

Fig. 4 Photo-responsive interconversion between doubly-threaded dimer and inclusion complex

and circular dichroism spectroscopy indicate that the supramolecular assemblies are formed from more than ten monomers through π–π interaction of the stilbene moieties (Fig. 3) [30]. An α-CD derivative modified with a stilbene moiety on the 6-position through an amide linkage exhibits different inclusion properties in the trans and cis states: the trans isomer forms favorably a doubly-threaded dimer, whereas the cis isomer forms rather strongly an inclusion complex with 1,10 -decane-1,10-diyldipyridinium dibromide because of a balance of the binding constants (Fig. 4) [31]. It has been reported that α-CD derivatives modified with a cinnamoyl moiety on the 2- and 3-positions through an ester linkage are interconverted spontaneously to each other and form alternating supramolecular oligomers [32]. α-CDs modified with a stilbene moiety on the 2- and 3-positions through an ester linkage are also interconverted to each other [33]. The 2-substituted isomer forms a doubly-threaded dimer in the trans state and supramolecular oligomers in the cis state. Contrastingly, the 3-substituted isomer forms supramolecular oligomers in the trans state and a doubly-threaded dimer in the cis state (Fig. 5). The complex formation of β-CD with a guest composed of ferrocene and azobenzene moieties linked through a 4,40 -bipyridinium linkage was investigated (Scheme 5) [34]. This system acts as a molecular switch responsive to photo and redox stimuli. Two β-CD molecules include the ferrocene and trans-azobenzene moieties of the guest, respectively. After the azobenzene moiety is isomerized from trans to cis by irradiation at 365 nm, the β-CD molecule preferably includes the ferrocene moiety because β-CD does not include the cis-azobenzene moiety. On the other hand, after the ferrocene moiety is oxidized to ferrocenium, a β-CD molecule includes the advantageous trans-azobenzene moiety because β-CD does not include the ferrocenium moiety.

Cyclodextrin-Based Molecular Machines

Fig. 5 Contrasting photo-responsive interconversions between doubly-threaded dimer and supramolecular oligomer

Scheme 5 A cyclodextrin-based molecular switch responsive to photo and redox stimuli

In addition, combinations of α- or β-CD, azobenzene moieties, and water soluble polymers provide photo-responsive hydrogel systems which undergo gel-to-sol and sol-to-gel transitions under light irradiation [35–39].

A. Hashidzume et al.

Scheme 6 A cyclodextrin-based molecular abacus

4.2

Cyclodextrin-Based Molecular Shuttles

Rotaxanes or pseudo-rotaxanes composed of axis molecules, in which two or more guest moieties (stations) are linked in series, can act as molecular shuttles because the rotor moiety can shuttle between the stations. A molecular abacus was realized using the molecular necklace formed from α-CD and poly(ethylene glycol) (PEG) reported by Harada et al. [40]. The molecular necklace was adsorbed on a molybdenum disulfide substrate and observed by scanning tunneling microscopy (STM). When α-CD molecules in the adsorbed molecular necklace are pushed by an STM tip, the α-CD molecules move along the PEG axis like beads in an abacus (Scheme 6) [41]. On the basis of the finding that cationic species act as electric barriers for α-CD [42], a molecular shuttle, i.e., a [2]rotaxane, was synthesized from α-CD and an axis molecule composed of two dodecamethylene units linked through a 4,40 -bipyridinium linkage (Scheme 7) [43]. Since the shuttling of α-CD between the stations in the [2]rotaxane is rather slow because of the electric barrier, the 1H NMR signals asscribable to the free and complexed stations are observed separately at room temperature both in D2O and in dimethyl sulfoxide-d6 (DMSO-d6). 1H NMR spectra measured in D2O at different temperatures are almost the same, indicating the shuttling of α-CD is slow in D2O because of hydrophobic interaction between the α-CD and stations. On the other hand, 1H NMR spectra measured in DMSO-d6 exhibited a coalescence of the signals due to the free and complexed stations at temperatures higher than ca. 130 C. Using the Eyring equation, the free energy of activation for the shuttling process of α-CD in the molecular shuttle was evaluated to be ca. 84 kJ mol1. Photo-responsive CD-based molecular suttles were reported using a combination of α-CD, azobenzene, and a nonresponsive guest (e.g., oligomethylene) moiety [44–47]. α-CD shuttles between azobenzene and nonresponsive guest moieties in

Cyclodextrin-Based Molecular Machines

Scheme 7 A cyclodextrin-based molecular shuttle

Fig. 6 An example of photo-responsive cyclodextrin-based molecular shuttles

response to light: α-CD is located on the azobenzene moiety in the trans state, whereas α-CD is located on the nonresponsive guest in its cis state of the azobenzene moiety (Fig. 6). A doubly photo-responsive CD-based molecular shuttle was synthesized using α-CD, azobenzene, and stilbene moieties as a molecular logic gate (Scheme 8) [48]. It should be noted that the azobenzene and stilbene moieties can be isomerized upon irradiation at different wavelengths: the azobenzene moiety is isomerized from trans to cis and from cis to trans under irradiation at 380 and 450 nm, respectively, and the stilbene moiety is isomerized from trans to cis and

A. Hashidzume et al.

Scheme 8 A photo-driven cyclodextrin-based molecular logic gate

from cis to trans under irradiation at 313 and 280 nm, respectively. When both the azobenzene and stilbene moieties take the trans forms, α-CD shuttles and includes both moieties. After trans-to-cis photoisomerization of either the azobenzene or the stilbene moiety, α-CD includes only the trans form. When both the moieties take the cis forms, α-CD includes neither the azobenzene nor the stilbene moiety, staying on the middle biphenyl moiety. A redox-responsive CD-based molecular shuttle was also synthesized from α-CD and a tetrathiafulvalene (TTF) moiety, which undergoes two-electron oxidation (Scheme 9) [49, 50]. In the reduced state of TTF, α-CD stays on the TTF moiety. The TTF moiety is oxidized chemically with hydrogen peroxide or electrochemically. In its oxidized state, α-CD stays on the triazole moiety.

4.3

Cyclodextrin-Based Molecular Rotational Motors

CD molecules in CD-based rotaxanes and pseudo-rotaxanes can rotate freely around the axis at room temperature because of the low rotational barrier. Thus, CD-based rotaxanes and pseudo-rotaxanes can be developed as molecular rotational motors, although it is still difficult to detect and control the rotational motion of the CD moiety in rotaxanes and pseudo-rotaxanes. A series of [2]rotaxanes were synthesized from α-CD derivatives and a diphenylacetylene axis molecule using trinitrobenzene as a stopper (Scheme 10). The rotational motion of α-CD moiety was investigated by NMR techniques [51]. The rotational correlation times (τc) for the axes and the rotors were separately evaluated using longitudinal relaxation

Cyclodextrin-Based Molecular Machines

Scheme 9 A redox-responsive cyclodextrin-based molecular shuttle

Scheme 10 The structures of axis and [2]rotaxanes, for which the rotational motion of α-CD moiety was investigated by NMR techniques

times determined by 13C NMR measured at different magnetic fields in DMSO-d6. The τc for the axis was shorter than that for the rotor, indicative of faster rotation of the axis. The differences in the reciprocal τc (Δ(1/τc)) for the axis and rotor of the [2]rotaxane of unmodified α-CD was larger than those for the other [2]rotaxanes of modified α-CD, indicating that the rotation of the axis relative to the rotor for the [2]rotaxane of unmodified α-CD is faster than those for the other [2]rotaxanes, presumably because of the steric hindrance between the stopper of the axis and the substituent on the rotor. Furthermore, the same type of [2]rotaxane possessing

A. Hashidzume et al. Scheme 11 A [2]rotaxane attached on a glass substrate for single molecular imaging

rhodamine B on α-CD was attached covalently onto a glass substrate for singlemolecular imaging (Scheme 11) [52]. The rotational motion of the rhodamine B-modified α-CD was detected by defocused wide-field imaging with total internal reflection fluorescence microscopy: the motion of the rhodamine B-modified α-CD is suspended under dry conditions, whereas the modified α-CD rotates (or vibrates) around the axis under wet conditions. CD-based catenanes can be used in molecular rotational motors if it is possible to control the position of the CD moiety in the catenanes by external stimuli. However, the movement of the CD molecule in catenanes has still been an underexamined subject of investigation. CD-based [2]- and [3]catenanes were first synthesized from methylated β-CD, 4,40 -diphenylene, and oligo(ethylene glycol) (OEG) moieties using ring closure by amide coupling reaction (Scheme 12). The two [2]catenanes and one-to-one mixture of [3]catenanes were fractionated by a combination of silica gel column chromatography and thin layer chromatography [11]. The [3]catenanes were further fractionated by reverse-phase high performance liquid chromatography (HPLC). 13C NMR spectra measured for the [3]catenanes in CDCl3 were indicative of rapid exchange of methylated β-CD in the rotaxanes on the 13C NMR timescale [12]. Another CD-based catenane was synthesized utilizing the formation of dimeric macrocycle between 4,40 -bis(4-pyridylmethoxy)biphenyl and (ethylenediamine)palladium(II) nitrate in the presence of β-CD (Scheme 13) [13].

Cyclodextrin-Based Molecular Machines

Scheme 12 Cyclodextrin-based catenanes [11, 12]

4.4

Cyclodextrin-Based Molecular Ratchets

Since a ratchet mechanically regulates the direction of motion of parts in machines, it is an important building block for machines. Thus, molecular ratchets may be an important building block of molecular machines, but only a few examples of CD-based molecular ratchets have been reported.

A. Hashidzume et al.

Scheme 13 A cyclodextrin-based catenane [13]

Scheme 14 A cyclodextrin-based molecular rotational ratchet

Several [2]rotaxanes were synthesized from 6-amino-α-CD, stilbene, and trinitrophenyl moieties. After linking the 6-amino-α-CD molecule covalently with the axis, the detailed structure of the rotaxane was investigated by various two-dimensional (2D) NMR techniques (Scheme 14) [53]. The rotational Overhauser enhancement and exchange spectroscopy (ROESY) for the [1]rotaxane of R¼H exhibited the uniform intensity of correlation signals between the stilbene protons and the C3 and C5 protons in the CD moiety, whereas the ROESY spectrum for the [1]rotaxane of R¼OCH3 showed different intensities of correlation signals. These observations indicate that the larger substituent (i.e., methoxy) on the stilbene moiety restricts the rotational motion of the α-CD moiety like a ratchet tooth. The formation of inclusion complexes of α-CD with several axis molecules composed of decamethylene and methyl-substituted pyridinium moieties was investigated by 1H NMR [54, 55]. NMR data measured for the axis molecule possessing 2-methylpyridinium and 3,5-dimethylpyridinium (a stopper) at 70 C have demonstrated that the 2-methyl group regulates kinetically the direction of

Cyclodextrin-Based Molecular Machines

Scheme 15 A cyclodextrin-based molecular translational ratchet

Scheme 16 A cyclodextrin-based molecular translational ratchet

inclusion of α-CD, presumably because of the steric effect: α-CD includes the axis from the wider side (Scheme 15). The 2-methyl group on the pyridinium also regulates the direction of inclusion of α-CD on a two-station axis composed of two decamethylene moieties linked through a 4,40 -bipyridinium linkage to form [2]- and [3]rotaxanes: α-CD includes the two-station axis preferably from the wider side (Scheme 16) [56]. The formation of a [2]rotaxane from α-CD with a two-station axis composed of two decamethylene moieties linked through a 2-methylpyridinium moiety was further investigated by 1H NMR to clarify the effect of the 2-methyl group on the translation of α-CD. Using 1H NMR data, the rate constants for translation were evaluated using a simplified kinetic model. The rate constant of translation of α-CD from the wider side was larger than that from the narrower side, indicating that the methyl substituent on the pyridinium linkage controls the shuttling rates of α-CD between the decamethylene stations to realize face selective translation (Fig. 7) [57].

A. Hashidzume et al.

Fig. 7 Movement of α-CD regulated by the methyl group on the middle pyridinium linker in a cyclodextrin-based molecular ratchet

4.5

Cyclodextrin-Based Molecular Knots

Cyclodextrins modified with guest moieties can form self-inclusion complexes, i.e., [1]rotaxanes, which are considered to be molecular knots. The formation of inclusion complexes of 6A-deoxy-6A-(N-methyl3-phenylpropionamido)-β-CD and 6A-deoxy-6A-(N-methylcinnamido)-β-CD with 1-adamantanol was investigated in detail by 1H NMR [58]. In the case of the 6A-deoxy-6A-(N-methyl-3-phenylpropionamido)-β-CD, the amide linkage preferably take the Z-form to form the stable self-inclusion complex (the molar ratio of the amide Z- and E-forms ¼ 25:1). In the presence of 1-adamantanol, the β-CD derivative forms a stable inclusion complex with 1-adamantanol, leading to a reduced relative stability of the amide Z-form (the molar ratio of the amide Z- and E-forms ¼ 2.4:1 in the presence of 3 equiv. of 1-adamantanol). These observations indicate that 1-adamantanol regulates the balance of amide Z- and E-forms (Scheme 17a). However, in the case of the 6A-deoxy-6A-(N-methylcinnamido)-β-CD, trans-to-cis and cis-to-trans photoisomerization of the cinnamoyl moiety switches the balance of amide Z- and E-forms. The amide linkage in the cinnamoyl cis isomer favorably adopts the Z-form to form a very stable selfinclusion complex (the molar ratio of the amide Z- and E-forms ¼ 100:1). In the presence of 1-adamantanol, the formation of complexes with 1-adamantanol reduces the relative stability of the amide Z-form (the molar ratio of the amide Z- and E-forms ¼ 2.6:1 in the presence of 3 equiv. of 1-adamantanol). In the case of the cinnamoyl trans isomer, however, 1-adamantanol does not regulate the balance of the amide Z- and E-forms significantly (the molar ratios of the amide Z- and E-forms ¼ 4.2:1 and 5.6:1 in the absence and presence of 3 equiv. of 1-adamantanol, respectively) (Scheme 17b). β-CD derivatives modified with a PEG-carrying cinnamoyl moiety at the 6-position through an ester linkage were synthesized [59, 60]. The β-CD derivatives form stable self-inclusion complexes, in which the cinnamoyl moiety is included in the β-CD cavity. In the presence of

Cyclodextrin-Based Molecular Machines

Scheme 17 Structural change of cyclodextrin-based molecular knots

1 equiv. of 1-adamantane carboxylic acid (AdCA), β-CD derivatives form stable inclusion complexes with AdCA. It should be noted that, in the presence of 0.5 equiv. of AdCA, the exchange between the self-inclusion complex and inclusion complex with AdCA was observed on the NMR time scale (Scheme 18). The exchange rate constants were determined by 1H NMR at different temperatures and 2D exchange spectroscopy to study the self-threading kinetics. The exchange rate constant decreases exponentially from 5.3  103 s1 to 3.2 s1 with increasing degree of polymerization of PEG from 2 to 230 at 30 C. The PEG-carrying β-CD derivative was further modified with an azobenzene moiety at the end of PEG, and the formation of self-inclusion complexes responsive to temperature and light was investigated (Scheme 19) [61]. In the case of the trans isomer of azobenzene moiety, the β-CD moiety includes preferably the cinnamoyl and azobenzene moieties at 1 and 60 C, respectively. When the temperature is further increased up to 80 C, the β-CD derivative of trans isomer takes a dethreading form. In the case of the cis isomer, the β-CD moiety includes advantageously the azobenzene moiety at ca. 30 C.

A. Hashidzume et al.

Scheme 18 Exchange between the self-inclusion complex and inclusion complex with AdCA

Scheme 19 A cyclodextrin-based self-inclusion complex responsive to temperature and light

Cyclodextrin-Based Molecular Machines Scheme 20 Cyclodextrinbased molecular puzzle rings

It is known that a glucopyranose unit in CDs is isomerized to an altropyranose unit during the preparation of CDs substituted with amine at the 3-position and the altropyranose unit takes favorably the 1C4 conformation [62]. Using the flexibility of 3-amino-CDs possessing an altropyranose unit, some interesting examples of self-inclusion complexes of CDs modified with a guest moiety at the 3-position through an amide linkage have been reported. α-CD derivatives modified with 4-substituted cis-cinnamoyl moieties at the 3-position through an amide linkage were reported as molecular puzzle rings (Scheme 20) [63]. Not only the α-CD derivative carrying the smallest substituent, i.e., an acetyl group, but also the other derivatives carrying larger substituents, i.e., 2,4,6-trinitrophenyl and admantyl groups, form self-inclusion complexes in D2O, in which the altropyranose unit takes the 4C1 conformation. It should be noted that 2,4,6-trinitrophenyl and adamantyl substituents pass through the α-CD cavity because of the flexibility of the α-CD moiety possessing an altropyranose unit. The kinetics of the formation of self-inclusion complexes for the acetyl and adamantyl derivatives was investigated by NMR exchange and UV spectroscopy, respectively. The rate constant of the formation of self-inclusion complex for the acetyl derivative was much larger (1.2 s1) than that for the adamantyl derivative (5.9  103 s1). Since the altropyranose unit in 3-amino-CD can flip, CD derivatives modified with a longer guest moiety possessing a bulky stopper at the end can form self-inclusion complexes by the flipping mechanism. [2]Rotaxane and [3]rotaxane were synthesized from unmodified α-CD and α-CD modified with an axis composed of decamethylene and stilbene moieties at the 3-position through an amide linkage, using an adamantyl group as a stopper [64]. The [2]rotaxane acts as a molecular reel: the modified α-CD in the [2]rotaxane includes the decamethylene moiety in water by the flipping mechanism, and the α-CD rotor thus moves from the decamethylene moiety to the stilbene moiety (Fig. 8). The activation free energy for the flipping was evaluated to be 89.4 kJ mol1 at 288 K. A symmetrical α-CD dimer was synthesized by amide coupling of 3-amino-α-CD and two undecanoic acid moieties linked by a 4,40 -bipyridinium moiety [65]. In water, the α-CD moieties include the decamethylene moieties by the flipping mechanism (Fig. 9).

A. Hashidzume et al. Fig. 8 Solvent-responsive self-inclusion of a [2] rotaxane: a molecular reel

Fig. 9 Solvent-responsive self-inclusion of a symmetrical α-CD dimer by the flipping mechanism

Series of symmetric CD dimers possessing a perylene fluorophore at the center were synthesized from 3-amino-CDs with 3,4,9,10-perylene tetracarboxylic dianhydride or with N,N0 -bis(6-carboxylhexyl)perylene-3,4,9,10-tetracarboxyl diimide [66]. In the case of the β-CD dimer possessing hexamethylene linkers, the self-inclusion structure formed by the flipping mechanism efficiently protects perylene fluorophores from self-quenching.

4.6

Cyclodextrin-Based Molecular Actuators

Muscle fibers are biological molecular actuators and possess the sarcomere structure, in which myosin filaments slide on actin filaments to produce force and movement. An important class of artificial molecular muscles is doubly-threaded dimers or Janus [2]rotaxanes [67]. A CD-based Janus [2]rotaxane possessing a long axis composed of hexamethylene and ureido moieties was synthesized from a doubly-threaded dimer of α-CD modified with a cinnamoyl moiety at the 6-position through an amide linkage (Scheme 21) [68]. The α-CD moieties in the Janus [2]rotaxane include the cinnamoyl moieties in DMSO, whereas the α-CD moieties include the hexamethylene moieties in a DMSO/water mixed solvent (1/1, v/v) presumably because of the enhanced solvophobic interaction. The hydrodynamic radii estimated by pulsed field gradient spin-echo (PGSE) NMR spectroscopy confirmed the size change. A photo-responsive Janus [2]rotaxane was synthesized utilizing α-CD modified with a stilbene moiety at the 6-position through an amide linkage as the basis of a photo-driven molecular muscle (Scheme 22) [69]. The trans,trans isomer was isomerized under irradiation at 350 nm to form the trans,cis and cis,cis isomers. The trans,cis and cis,cis isomers were purified by HPLC. The structures of the

Cyclodextrin-Based Molecular Machines

Scheme 21 A chemical-responsive cyclodextrin-based molecular actuator

isomers were investigated in detail by NMR techniques. In the trans,trans isomer, both the trans-stilbene moieties are included in the α-CD moieties. In the trans,cis isomer, the trans-stilbene moiety is still included in the α-CD moiety, whereas the cis-stilbene moiety is not. In the cis,cis isomer, both the cis-stilbene moieties exist outside the α-CD cavities. The trans-to-cis and cis-to-trans photoisomerization of stilbene moieties is repeatable by cycles of irradiation with 350 nm light followed by 254 nm light. To obtain a larger change in dimension, a doubly-threaded dimer and Janus [2]rotaxanes were synthesized using α-CD modified with azobenzene and heptamethylene moieties linked with OEG (Scheme 23) [70, 71]. The azobenzene moieties of the dimer and Janus [2]rotaxanes are isomerized from trans to cis under irradiation at 365 nm and from cis to trans under irradiation at 430 nm. PGSE NMR data have indicated that the hydrodynamic radius of the trans,trans isomer is larger than that for the cis,cis isomer by ca. 20–30%. Apart from doubly-threaded dimers and Janus [2]rotaxanes, other types of molecular actuators have been reported. A mechanically switchable bistable [1] rotaxane was synthesized from β-CD modified with an azobenzene moiety and a cobalt(II) salen unit (Scheme 24) [72]. In the trans state of azobenzene moieties, β-CD moieties include the azobenzene moieties, and the [1]rotaxane adopts an expanded form. Under irradiation at 365 nm, the trans-azobenzene moieties are isomerized to the cis isomer. In the cis state, the β-CD moieties are located close to the cobalt(II) salen unit, and the [1]rotaxane takes a contracted form. Very recently, CD-based macroscopic molecular actuators were realized using hydrogels possessing covalent and stimuli-responsive non-covalent crosslinks [73, 74]. A quarterpolymer was synthesized from acrylamide, N,N0 -methylenebis(acrylamide), an α-CD monomer, and an azobenzene monomer in DMSO to form a gel (Scheme 25) [73]. When the solvent is replaced with water, the volume of gel decreases, indicative of an increased cross-link density by the formation of

A. Hashidzume et al. Scheme 22 A photo-driven cyclodextrin-based molecular muscle

inclusion complexes of α-CD and trans-azobenzene moieties. The transazobenzene moieties are isomerized to the cis isomer under irradiation at 365 nm. Since the α-CD moieties do not include any cis-azobenzene moieties, the non-covalent crosslinks are cleaved, resulting in an increase in the volume of hydrogel. These volume changes are repeatable by cycles of irradiation with 365 and 430 nm light. Furthermore, a photo-regulated actuator was realized using a ribbon-shaped hydrogel. Similarly, a quarterpolymer of acrylamide, N,N0 methylenebis(acrylamide), a β-CD monomer, and a ferrocene monomer was reported as a redox-responsive macroscopic molecular actuator (Scheme 26) [74]. In the reduced state of ferrocene moiety, the β-CD includes the ferrocene moieties to form non-covalent crosslinks. When the ferrocene moieties are oxidized to ferrocenium with ceric ammonium nitrate, the β-CD does not include the ferrocenium moieties and the non-covalent crosslinks are cleaved, resulting in an

Cyclodextrin-Based Molecular Machines

Scheme 23 A photo-driven cyclodextrin-based molecular actuator

Scheme 24 A photo-driven cyclodextrin-based molecular actuator

A. Hashidzume et al.

Scheme 25 Chemical structure of a hydrogel which acts as a photo-driven macroscopic molecular actuator

Scheme 26 Chemical structure of a hydrogel which acts as a redox-driven macroscopic molecular actuator

increase in the volume of hydrogel. A strip of this hydrogel did mechanical work (2.0 μW) to a weight of 291 mg upon reduction of the ferrocenium moieties.

4.7

Cyclodextrin-Based Molecular Sensors

The photophysical and photochemical behavior of dyes, i.e., chromophores and fluorophores, depends on their environment [75]. Since CD cavities provide a less polar medium and/or protect the excited state of dyes, the formation of inclusion complexes of CDs with dyes often causes a shift of the absorption band and/or an increase in the fluorescence intensity. Thus, the molecular recognition ability of CDs combined with dyes can allow one to build molecular sensors [76, 77]. There have been three categories of CD-based molecular sensors identified: (1) CD derivatives modified with a dye (Fig. 10a) [78–84], (2) polymers doubly modified with CD and dye moieties (Fig. 10b) [85–89], and (3) polyrotaxanes carrying CD molecules modified with a dye (Fig. 10c) [90]. In the case of categories (1) and (2), the dye (R) included in the CD cavity is ejected in the presence of the target molecules, resulting in a change in the absorption and/or fluorescence of the dye.

Cyclodextrin-Based Molecular Machines Fig. 10 Conceptual illustration of cyclodextrinbased molecular sensors: CD derivatives modified with a dye, where R denotes a dye moiety (a), polymers doubly modified with CD and dye moieties (b), and polyrotaxanes carrying CD derivatives modified with a dye, where D and A denote donor and acceptor residues, respectively (c)

In the case of category (3), the CD molecules carrying an acceptor (A) are dissociated by complexation with the target molecule, leading to a reduction of fluorescence resonance energy transfer from the donor (D) to the A moieties.

4.8

Cyclodextrin-Based Molecular Printboards

Self-assembled monolayers formed from β-CD derivatives adsorbed on a surface (e.g., gold and silica) [91–93] have been known as molecular printboards (Scheme 27) [94–96]. Various patterns on the micrometer scale can be formed on the molecular printboard utilizing complexation of the β-CD moieties with multivalent guest molecules, i.e., molecular inks, using the soft lithography technique [97–100]. Multivalency may provide stronger binding. Redox-responsive printing on the molecular printboard was reported using redox-responsive molecular inks, i.e., poly(amidoamine) dendrimers possessing ferrocene moieties on the exterior. The ferrocene-carrying dendrimers are adsorbed on the molecular printboard in their reduced state. The ferrocene moieties adsorbed can be oxidized electrochemically, and then the dendrimers are desorbed [101–106]. The molecular printboard technique is also a powerful tool to immobilize proteins on a surface for biotechnological applications. Several proteins have been immobilized on the molecular printboard using complexation of a hexahistidine tag with nickel nitrilotriacetate-carrying adamantane molecules adsorbed on the molecular printboard [107, 108] or using complexation of streptavidin with biotin-carrying adamantane dimer molecules adsorbed on the molecular printboard [107, 109–112].

A. Hashidzume et al.

Scheme 27 Molecular printboard (upper) and molecular inks (lower)

4.9

Cyclodextrin-Based Controlled Release Systems

Since CDs can capture various molecules, including drug molecules, and release them slowly depending on the binding constant, CD-based stimuli-responsive rotaxanes and pseudo-rotaxanes can be used as nanocarriers for controlled release [113–116]. Recently, stimuli-responsive rotaxanes and pseudo-rotaxanes were developed as nanovalves for controlled release [117–119]. Mesoporous silica nanoparticles can contain drug molecules inside the pores. The drug molecules can be trapped in the mesoporous silica nanoparticles by attaching nanovalves, i.e., stimuli-responsive CD-based rotaxanes or pseudo-rotaxanes, onto the surface of nanoparticles. When the nanovalves are opened, i.e., rotaxanes are decomposed or pseudo-rotaxanes are

Cyclodextrin-Based Molecular Machines

Fig. 11 Conceptual illustration of cyclodextrin-based controlled release of drugs loaded in mesoporous silica nanoparticles

dissociated, in response to external stimuli, the drug molecules inside the mesoporous silica nanoparticles are released from the pores (Fig. 11). This type of CD-based controlled release systems responsive to pH [120–124], enzyme [125–127], redox [128–130], and light [131, 132] have been realized.

4.10

Cyclodextrin-Based Artificial Enzymes

Using the molecular recognition ability of CDs, CD-based artificial enzymes have been widely investigated [133–135]. It has been reported that CDs catalyze ring opening polymerization of lactones with size selectivity: β-butyrolactone is polymerized efficiently by α-CD and β-CD, and γ-valerolactone and ε-caprolactone produce polyesters effectively with β-CD [136–138]. The CD-catalyzed ring opening polymerization yields polyesters carrying a CD moiety at the chain end, and the monomer molecule included in the CD cavity is inserted between the CD moiety and the polyester chain in the propagation step. During the ring opening polymerization, the formation of poly-pseudorotaxane from the polyester and excess CD molecules is critical because the polypseudo-rotaxane structure reduces the steric hindrance around the CD cavity at the chain end (Scheme 28) [139]. On the basis of these findings, various CD dimers were employed for ring opening polymerization of lactones to clarify the importance of pseudo-rotaxane structure [140]. The efficiency of ring opening polymerization is strongly dependent on the length of linker between the two CD moieties: the CD dimer linked with a cis-stilbene linkage exhibits the highest efficiency for γ-valerolactone because the length of the cis-stilbene linkage might be appropriate to form the pseudo-rotaxane structure in the early stage of polymerization (Scheme 29).

A. Hashidzume et al.

Scheme 28 Ring opening polymerization of γ-valerolactone initiated by β-cyclodextrin

Scheme 29 Ring opening polymerization of γ-valerolactone initiated by a cyclodextrin dimer linked through cis-stilbenen

5 Concluding Remarks This chapter has overviewed CD-based molecular machines, in which the categories of CD-based molecular machines (Sect. 2), external stimuli for CD-based molecular machines (Sect. 3), and typical examples of CD-based molecular machines (Sect. 4) were briefly described. As stated in the introduction, biological systems are based on highly functional molecular machines composed of biological macromolecules. Compared to the biological molecular machines, artificial ones are still primitive. Therefore scientists should accumulate and combine their wisdom for construction of highly functional artificial molecular machines to open the door to “The Molecular Industrial Revolution.” We believe that CDs are an important building block of such highly functional artificial molecular machines.

References 1. Saenger W, Jl J, Gessler K, Steiner T, Hoffmann D, Sanbe H, Koizumi K, Smith SM, Takaha T (1998) Structures of the common cyclodextrins and their larger analogues beyond the doughnut. Chem Rev 98(5):1787–1802. doi:10.1021/cr9700181 2. Bender ML, Komiyama M (1978) Cyclodextrin chemistry, vol 6, Reactivity and structure concepts in organic chemistry. Springer, Berlin 3. Szejtli J (1982) Cyclodextrins and their inclusion complexes. Akade´miai Kiado´, Budapest 4. Szejtli J, Osa T (eds) (1996) Cyclodextrins, vol 3, Comprehensive supramolecular chemistry. Pergamon, Oxford

Cyclodextrin-Based Molecular Machines 5. Harada A (1996) Cyclodextrins. In: Semlyen JA (ed) Large ring molecules. Wiley, Chichester, pp 407–432 6. Dodziuk H (ed) (2006) Cyclodextrins and their complexes: chemistry, analytical methods, applications. Wiley-VCH, Weinheim 7. Harada A (2001) Cyclodextrin-based molecular machines. Acc Chem Res 34(6):456–464. doi:10.1021/ar000174l 8. Easton CJ, Lincoln SF, Barr L, Onagi H (2004) Molecular reactors and machines: applications, potential, and limitations. Chem Eur J 10(13):3120–3128. doi:10.1002/chem. 200305768 9. Haider JM, Pikramenou Z (2005) Photoactive metallocyclodextrins: sophisticated supramolecular arrays for the construction of light activated miniature devices. Chem Soc Rev 34(2):120–132. doi:10.1039/B203904B 10. Tian H, Wang Q-C (2011) Cyclodextrin-based switches. In: Feringa BL, Browne WR (eds) Molecular switches, vol 1. Wiley-VCH, Weinheim, pp 301–319. doi:10.1002/ 9783527634408.ch9 11. Armspach D, Ashton PR, Moore CP, Spencer N, Stoddart JF, Wear TJ, Williams DJ (1993) The self-assembly of catenated cyclodextrins. Angew Chem Int Ed Engl 32(6):854–858. doi:10.1002/anie.199308541 12. Armspach D, Ashton PR, Ballardini R, Balzani V, Godi A, Moore CP, Prodi L, Spencer N, Stoddart JF, Tolley MS, Wear TJ, Williams DJ, Stoddart JF (1995) Catenated cyclodextrins. Chem Eur J 1(1):33–55. doi:10.1002/chem.19950010109 13. Lim CW, Sakamoto S, Yamaguchi K, Hong J-I (2004) Versatile formation of [2]catenane and [2]pseudorotaxane structures; threading and noncovalent stoppering by a self-assembled macrocycle. Org Lett 6(7):1079–1082. doi:10.1021/ol036127l 14. Hashidzume A, Harada A (2012) Stimuli-responsive systems. In: Harada A (ed) Supramolecular polymer chemistry. Wiley-VCH, Weinheim, pp 231–267. doi:10.1002/ 9783527639786.ch11 15. Izawa H, Kawakami K, Sumita M, Tateyama Y, Hill JP, Ariga K (2013) β-Cyclodextrincrosslinked alginate gel for patient-controlled drug delivery systems: regulation of host–guest interactions with mechanical stimuli. J Mater Chem B 1(16):2155–2161. doi:10.1039/ C3TB00503H 16. Cramer F, Hettler H (1967) Inclusion compounds of cyclodextrins. Naturwissenschaften 54 (24):625–632. doi:10.1007/BF01142413 17. Bortolus P, Monti S (1987) Cis trans photoisomerization of azobenzene-cyclodextrin inclusion complexes. J Phys Chem 91(19):5046–5050. doi:10.1021/j100303a032 18. Taura D, Li S, Hashidzume A, Harada A (2010) Formation of side-chain hetero-polypseudorotaxane composed of α- and β-cyclodextrins with a water-soluble polymer bearing two recognition sites. Macromolecules 43(4):1706–1713. doi:10.1021/ma902712u 19. Yamaguchi H, Kobayashi Y, Kobayashi R, Takashima Y, Hashidzume A, Harada A (2012) Photoswitchable gel assembly based on molecular recognition. Nat Commun 3:603. doi:10. 1038/ncomms1617 20. Harada A, Takahashi S (1984) Preparation and properties of cyclodextrin-ferrocene inclusion complexes. J Chem Soc Chem Commun (10):645–646. doi:10.1039/C39840000645 21. Harada A, Hu Y, Yamamoto S, Takahashi S (1988) Preparation and properties of inclusion compounds of ferrocene and its derivatives with cyclodextrins. J Chem Soc Dalton Trans (3):729–732. doi:10.1039/DT9880000729 22. McCormack S, Russell NR, Cassidy JF (1992) Cyclic voltammetry of ferrocene carboxylic acid cyclodextrin inclusion complexes. Electrochim Acta 37(11):1939–1944. doi:10.1016/ 0013-4686(92)87106-A 23. Osella D, Carretta A, Nervi C, Ravera M, Gobetto R (2000) Inclusion complexes of ferrocenes and β-cyclodextrins. Critical appraisal of the electrochemical evaluation of formation constants. Organometallics 19(14):2791–2797. doi:10.1021/om0001366

A. Hashidzume et al. 24. Gonza´lez B, Cuadrado I, Alonso B, Casado CM, Mora´n M, Kaifer AE (2002) Mixed cobaltocenium  ferrocene heterobimetallic complexes and their binding interactions with β-cyclodextrin. A three-state, host  guest system under redox control. Organometallics 21 (17):3544–3551. doi:10.1021/om0202064 25. Becuwe M, Cazier F, Bria M, Woisel P, Delattre F (2007) Tuneable fluorescent marker appended to β-cyclodextrin: a pH-driven molecular switch. Tetrahedron Lett 48(35): 6186–6188. doi:10.1016/j.tetlet.2007.06.143 26. Chakrabarti S, Mukhopadhyay P, Lin S, Isaacs L (2007) Reconfigurable four-component molecular switch based on pH-controlled guest swapping. Org Lett 9(12):2349–2352. doi:10. 1021/ol070730c 27. Omori K, Takashima Y, Yamaguchi H, Harada A (2011) pH responsive [2]rotaxanes with 6-modified-α-cyclodextrins. Chem Lett 40(7):758–759. doi:10.1246/cl.2011.758 28. Ma X, Cao J, Wang Q, Tian H (2011) Photocontrolled reversible room temperature phosphorescence (RTP) encoding β-cyclodextrin pseudorotaxane. Chem Commun 47(12):3559–3561. doi:10.1039/C0CC05488G 29. Kuad P, Miyawaki A, Takashima Y, Yamaguchi H, Harada A (2007) External stimulusresponsive supramolecular structures formed by a stilbene cyclodextrin dimer. J Am Chem Soc 129(42):12630–12631. doi:10.1021/ja075139p 30. Yamauchi K, Takashima Y, Hashidzume A, Yamaguchi H, Harada A (2008) Switching between supramolecular dimer and nonthreaded supramolecular self-assembly of stilbene amide-α-cyclodextrin by photoirradiation. J Am Chem Soc 130(15):5024–5025. doi:10.1021/ ja7113135 31. Wang Z, Takashima Y, Yamaguchi H, Harada A (2011) Photoresponsive formation of pseudo[2]rotaxane with cyclodextrin derivatives. Org Lett 13(16):4356–4359. doi:10.1021/ ol201575x 32. Tomimasu N, Kanaya A, Takashima Y, Yamaguchi H, Harada A (2009) Social self-sorting: alternating supramolecular oligomer consisting of isomers. J Am Chem Soc 131(34): 12339–12343. doi:10.1021/ja903988c 33. Kanaya A, Takashima Y, Harada A (2011) Double-threaded dimer and supramolecular oligomer formed by stilbene modified cyclodextrin: effect of acyl migration and photostimuli. J Org Chem 76(2):492–499. doi:10.1021/jo101936t 34. Zhu L, Zhang D, Qu D, Wang Q, Ma X, Tian H (2010) Dual-controllable stepwise supramolecular interconversions. Chem Commun 46(15):2587–2589. doi:10.1039/b926323c 35. Tomatsu I, Hashidzume A, Harada A (2005) Photoresponsive hydrogel system utilizing molecular recognition of α-cyclodextrin. Macromolecules 38(12):5223–5227. doi:10.1021/ ma050670v 36. Tomatsu I, Hashidzume A, Harada A (2006) Contrast viscosity changes upon photoirradiation for mixtures of poly(acrylic acid)-based α-cyclodextrin and azobenzene polymers. J Am Chem Soc 128(7):2226–2227. doi:10.1021/ja058345a 37. Tamesue S, Takashima Y, Yamaguchi H, Shinkai S, Harada A (2010) Photoswitchable supramolecular hydrogels formed by cyclodextrins and azobenzene polymers. Angew Chem Int Ed 49(41):7461–7464. doi:10.1002/anie.201003567 38. Tamesue S, Takashima Y, Yamaguchi H, Shinkai S, Harada A (2011) Photochemically controlled supramolecular curdlan/single-walled carbon nanotube composite gel: preparation of molecular distaff by cyclodextrin modified curdlan and phase transition control. Eur J Org Chem (15):2801–2806. doi:10.1002/ejoc.201100077 39. Zhao Y-L, Stoddart JF (2009) Azobenzene-based light-responsive hydrogel system. Langmuir 25(15):8442–8446. doi:10.1021/la804316u 40. Harada A, Li J, Kamachi M (1992) The molecular necklace: a rotaxane containing many threaded α-cyclodextrins. Nature 356(6367):325–327. doi:10.1038/356325a0 41. Shigekawa H, Miyake K, Sumaoka J, Harada A, Komiyama M (2000) The molecular abacus: STM manipulation of cyclodextrin necklace. J Am Chem Soc 122(22):5411–5412. doi:10. 1021/ja000037j

Cyclodextrin-Based Molecular Machines 42. Kawaguchi Y, Harada A (2000) An electric trap: a new method for entrapping cyclodextrin in a rotaxane structure. J Am Chem Soc 122(15):3797–3798. doi:10.1021/ja9943647 43. Kawaguchi Y, Harada A (2000) A cyclodextrin-based molecular shuttle containing energetically favored and disfavored portions in its dumbbell component. Org Lett 2(10):1353–1356. doi:10. 1021/ol0055667 44. Murakami H, Kawabuchi A, Matsumoto R, Ido T, Nakashima N (2005) A multi-mode-driven molecular shuttle: photochemically and thermally reactive azobenzene rotaxanes. J Am Chem Soc 127(45):15891–15899. doi:10.1021/ja053690l 45. Wan P, Jiang Y, Wang Y, Wang Z, Zhang X (2008) Tuning surface wettability through photocontrolled reversible molecular shuttle. Chem Commun (44):5710–5712. doi:10.1039/ B811729B 46. Zhu L, Lu M, Qu D, Wang Q, Tian H (2011) Coordination-assembly for quantitative construction of bis-branched molecular shuttles. Org Biomol Chem 9(11):4226–4233. doi:10.1039/C0OB01124J 47. Hu J, Hashidzume A, Harada A (2011) Photoregulated switching of the recognition site of α-cyclodextrin in a side chain polyrotaxane bearing two recognition sites linked with oligo (ethylene glycol). Macromol Chem Phys 212(10):1032–1038. doi:10.1002/macp.201100029 48. Qu D-H, Wang Q-C, Tian H (2005) A half adder based on a photochemically driven [2] rotaxane. Angew Chem Int Ed 44(33):5296–5299. doi:10.1002/anie.200501215 49. Zhao Y-L, Dichtel WR, Trabolsi A, Saha S, Aprahamian I, Stoddart JF (2008) A redoxswitchable α-cyclodextrin-based [2]rotaxane. J Am Chem Soc 130(34):11294–11296. doi:10. 1021/ja8036146 50. Zhang Q, Tu Y, Tian H, Zhao Y-L, Stoddart JF, Ågren H (2010) Working mechanism for a redox switchable molecular machine based on cyclodextrin: a free energy profile approach. J Phys Chem B 114(19):6561–6566. doi:10.1021/jp102834k 51. Nishimura D, Oshikiri T, Takashima Y, Hashidzume A, Yamaguchi H, Harada A (2008) Relative rotational motion between α-cyclodextrin derivatives and a stiff axle molecule. J Org Chem 73(7):2496–2502. doi:10.1021/jo702237q 52. Nishimura D, Takashima Y, Aoki H, Takahashi T, Yamaguchi H, Ito S, Harada A (2008) Single-molecule imaging of rotaxanes immobilized on glass substrates: observation of rotary movement. Angew Chem Int Ed 47(32):6077–6079. doi:10.1002/anie.200801431 53. Onagi H, Blake CJ, Easton CJ, Lincoln SF (2003) Installation of a ratchet tooth and pawl to restrict rotation in a cyclodextrin rotaxane. Chem Eur J 9(24):5978–5988. doi:10.1002/chem. 200305280 54. Oshikiri T, Takashima Y, Yamaguchi H, Harada A (2005) Kinetic control of threading of cyclodextrins onto axle molecules. J Am Chem Soc 127(35):12186–12187. doi:10.1021/ ja053532u 55. Yamaguchi H, Oshikiri T, Harada A (2006) Rotaxanes with unidirectional cyclodextrin array. J Phys Condens Matter 18(33):S1809. doi:10.1088/0953-8984/18/33/S03 56. Oshikiri T, Takashima Y, Yamaguchi H, Harada A (2007) Face-selective [2]- and [3] rotaxanes: kinetic control of the threading direction of cyclodextrins. Chem Eur J 13(25): 7091–7098. doi:10.1002/chem.200601657 57. Oshikiri T, Yamaguchi H, Takashima Y, Harada A (2009) Face selective translation of a cyclodextrin ring along an axle. Chem Commun (37):5515–5517. doi:10.1039/b906425g 58. Coulston RJ, Onagi H, Lincoln SF, Easton CJ (2006) Harnessing the energy of molecular recognition in a nanomachine having a photochemical on/off switch. J Am Chem Soc 128 (46):14750–14751. doi:10.1021/ja0651761 59. Inoue Y, Miyauchi M, Nakajima H, Takashima Y, Yamaguchi H, Harada A (2006) Selfthreading of a poly(ethylene glycol) chain in a cyclodextrin-ring: control of the exchange dynamics by chain length. J Am Chem Soc 128(28):8994–8995. doi:10.1021/ja061095t 60. Inoue Y, Miyauchi M, Nakajima H, Takashima Y, Yamaguchi H, Harada A (2007) Selfthreading and dethreading dynamics of poly(ethylene glycol)-substituted cyclodextrins with different chain lengths. Macromolecules 40(9):3256–3262. doi:10.1021/ma070095q

A. Hashidzume et al. 61. Inoue Y, Kuad P, Okumura Y, Takashima Y, Yamaguchi H, Harada A (2007) Thermal and photochemical switching of conformation of poly(ethylene glycol)-substituted cyclodextrin with an azobenzene group at the chain end. J Am Chem Soc 129(20):6396–6397. doi:10. 1021/ja071717q 62. Ikeda H, Nagano Y, DU Y-Q, Ikeda T, Toda F (1990) Modifications of the secondary hydroxyl side of α-cyclodextrin and NMR studies of them. Tetrahedron Lett 31(35): 5045–5048. doi:10.1016/S0040-4039(00)97802-X 63. Miyawaki A, Kuad P, Takashima Y, Yamaguchi H, Harada A (2008) Molecular puzzle ring: pseudo[1]rotaxane from a flexible cyclodextrin derivative. J Am Chem Soc 130(50): 17062–17069. doi:10.1021/ja806620z 64. Yamauchi K, Miyawaki A, Takashima Y, Yamaguchi H, Harada A (2010) A molecular reel: shuttling of a rotor by tumbling of a macrocycle. J Org Chem 75(4):1040–1046. doi:10.1021/ jo902393n 65. Yamauchi K, Miyawaki A, Takashima Y, Yamaguchi H, Harada A (2010) Switching from altro-α-cyclodextrin dimer to pseudo[1]rotaxane dimer through tumbling. Org Lett 12(6): 1284–1286. doi:10.1021/ol1001736 66. Takashima Y, Fukui Y, Otsubo M, Hamada N, Yamaguchi H, Yamamoto H, Harada A (2012) Emission properties of cyclodextrin dimers linked with perylene diimide—effect of cyclodextrin tumbling. Polym J 44(3):278–285. doi:10.1038/pj.2011.128 67. Fujimoto T, Sakata Y, Kaneda T (2000) The first Janus [2]rotaxane. Chem Commun (21): 2143–2144. doi:10.1039/b006758j 68. Tsukagoshi S, Miyawaki A, Takashima Y, Yamaguchi H, Harada A (2007) Contraction of supramolecular double-threaded dimer formed by α-cyclodextrin with a long alkyl chain. Org Lett 9(6):1053–1055. doi:10.1021/ol063078e 69. Dawson RE, Lincoln SF, Easton CJ (2008) The foundation of a light driven molecular muscle based on stilbene and α-cyclodextrin. Chem Commun (34):3980–3982. doi:10.1039/B809014A 70. Li S, Taura D, Hashidzume A, Takashima Y, Yamaguchi H, Harada A (2010) Photocontrolled size changes of doubly-threaded dimer based on an α-cyclodextrin derivative with two recognition sites. Chem Lett 39(3):242–243. doi:10.1246/cl.2010.242 71. Li S, Taura D, Hashidzume A, Harada A (2010) Light-switchable Janus [2]rotaxanes based on α-cyclodextrin derivatives bearing two recognition sites linked with oligo(ethylene glycol). Chem Asian J 5(10):2281–2289. doi:10.1002/asia.201000169 72. Gao C, Ma X, Zhang Q, Wang Q, Qu D, Tian H (2011) A light-powered stretch-contraction supramolecular system based on cobalt coordinated [1]rotaxane. Org Biomol Chem 9(4): 1126–1132. doi:10.1039/C0OB00764A 73. Takashima Y, Hatanaka S, Otsubo M, Nakahata M, Kakuta T, Hashidzume A, Yamaguchi H, Harada A (2012) Expansion-contraction of photoresponsive artificial muscle regulated by host-guest interactions. Nat Commun 3:1270. doi:10.1038/ncomms2280 74. Nakahata M, Takashima Y, Hashidzume A, Harada A (2013) Redox-generated mechanical motion of a supramolecular polymeric actuator based on host–guest interactions. Angew Chem Int Ed 52(22):5731–5735. doi:10.1002/anie.201300862 75. Turro NJ (1991) Modern molecular photochemistry. University Science, Sausalito 76. Ueno A (1996) Fluorescent cyclodextrins for molecule sensing. Supramol Sci 3(1–3):31–36. doi:10.1016/0968-5677(96)00016-8 77. Ogoshi T, Harada A (2008) Chemical sensors based on cyclodextrin derivatives. Sensors 8 (8):4961–4982. doi:10.3390/s8084961 78. Ueno A, Kuwabara T, Nakamura A, Toda F (1992) A modified cyclodextrin as a guest responsive colour-change indicator. Nature 356(6365):136–137. doi:10.1038/356136a0 79. Ikeda H, Nakamura M, Ise N, Oguma N, Nakamura A, Ikeda T, Toda F, Ueno A (1996) Fluorescent cyclodextrins for molecule sensing: fluorescent properties, NMR characterization, and inclusion phenomena of N-dansylleucine-modified cyclodextrins. J Am Chem Soc 118 (45):10980–10988. doi:10.1021/ja960183i

Cyclodextrin-Based Molecular Machines 80. Hamada F, Minato S, Osa T, Ueno A (1997) Fluorescent sensors for molecules. Guestresponsive monomer and excimer fluorescence of 6A,6B-; 6A,6C-; 6A,6D-; and 6A,6E-bis (2-naphthylsulfonyl)-γ-cyclodextrins. Bull Chem Soc Jpn 70(6):1339–1346. doi:10.1246/ bcsj.70.1339 81. Weidner S, Pikramenou Z (1998) Photoactive ruthenium(II) cyclodextrins responsive to guest binding. Chem Commun (14):1473–1474. doi:10.1039/A802301H 82. Nakashima H, Takenaka Y, Higashi M, Yoshida N (2001) Fluorescent behaviour in host– guest interactions. Part 2. Thermal and pH-dependent sensing properties of two geometric isomers of fluorescent amino-β-cyclodextrin derivatives. J Chem Soc Perkin Trans 2(11): 2096–2103. doi:10.1039/B105875B 83. Huo C, Chambron J-C, Meyer M (2008) Dual emission of a bis(pyrene)-functionalized, perbenzylated β-cyclodextrin. New J Chem 32(9):1536–1542. doi:10.1039/B803144D 84. Ogoshi T, Takashima Y, Yamaguchi H, Harada A (2006) Cyclodextrin-grafted poly-(phenylene ethynylene) with chemically-responsive properties. Chem Commun (35):3702–3704. doi:10. 1039/b605804c 85. Toyoda T, Matsumura S, Mihara H, Ueno A (2000) Guest-responsive excimer emission in an α-helix peptide bearing γ-cyclodextrin and two naphthalene units. Macromol Rapid Commun 21(8):485–488. doi:10.1002/(sici)1521-3927(20000501)21:83.0.co;2-o 86. Toyoda T, Mihara H, Ueno A (2002) Fluorescent cyclodextrin/peptide hybrids with a novel guest-responsive chemosensor in the peptide side chain. Macromol Rapid Commun 23(15): 905–908. doi:10.1002/1521-3927(20021001)23:153.0.co;2-o 87. Hossain MA, Matsumura S, Kanai T, Hamasaki K, Mihara H, Ueno A (2000) Association of α-helix peptides that have γ-cyclodextrin and pyrene units in their side chain, and induction of dissociation of the association dimer by external stimulant molecules. J Chem Soc Perkin Trans 2(7):1527–1533. doi:10.1039/B001090L 88. Hossain M, Takahashi K, Mihara H, Ueno A (2002) Molecule-responsive fluorescent sensors of α-helix peptides bearing α-cyclodextrin, pyrene and nitrobenzene units in their side chains. J Incl Phenom Macrocycl Chem 43(3–4):271–277. doi:10.1023/a:1021242225087 89. Hossain MA, Mihara H, Ueno A (2003) Fluorescence resonance energy transfer in a novel cyclodextrin-peptide conjugate for detecting steroid molecules. Bioorg Med Chem Lett 13 (24):4305–4308. doi:10.1016/j.bmcl.2003.09.051 90. Tamura M, Ueno A (2000) Energy transfer and guest responsive fluorescence spectra of polyrotaxane consisting of α-cyclodextrins bearing naphthyl moieties. Bull Chem Soc Jpn 73 (1):147–154. doi:10.1246/bcsj.73.147 91. Beulen MWJ, Bu¨gler J, Lammerink B, Geurts FAJ, Biemond EMEF, van Leerdam KGC, van Veggel FCJM, Engbersen JFJ, Reinhoudt DN (1998) Self-assembled monolayers of heptapodant β-cyclodextrins on gold. Langmuir 14(22):6424–6429. doi:10.1021/la980936+ 92. Scho¨nherr H, Chechik V, Stirling CJM, Vancso GJ (2000) Monitoring surface reactions at an AFM tip: an approach to follow reaction kinetics in self-assembled monolayers on the nanometer scale. J Am Chem Soc 122(15):3679–3687. doi:10.1021/ja994040i 93. Beulen MWJ, Bu¨gler J, de Jong MR, Lammerink B, Huskens J, Scho¨nherr H, Vancso GJ, Boukamp BA, Wieder H, Offenha¨user A, Knoll W, van Veggel FCJM, Reinhoudt DN (2000) Host-guest interactions at self-assembled monolayers of cyclodextrins on gold. Chem Eur J 6 (7):1176–1183. doi:10.1002/(sici)1521-3765(20000403)6:73.0. co;2-1 94. Huskens J, Deij MA, Reinhoudt DN (2002) Attachment of molecules at a molecular printboard by multiple host–guest interactions. Angew Chem Int Ed 41(23):4467–4471. doi:10.1002/1521-3773(20021202)41:233.0.co;2-c 95. Ludden MJW, Reinhoudt DN, Huskens J (2006) Molecular printboards: versatile platforms for the creation and positioning of supramolecular assemblies and materials. Chem Soc Rev 35(11):1122–1134. doi:10.1039/B600093M 96. Crespo-Biel O, Ravoo BJ, Huskens J, Reinhoudt DN (2006) Writing with molecules on molecular printboards. Dalton Trans (23):2737–2741. doi:10.1039/b517699a

A. Hashidzume et al. 97. Auletta T, Dordi B, Mulder A, Sartori A, Onclin S, Bruinink CM, Pe´ter M, Nijhuis CA, Beijleveld H, Scho¨nherr H, Vancso GJ, Casnati A, Ungaro R, Ravoo BJ, Huskens J, Reinhoudt DN (2004) Writing patterns of molecules on molecular printboards. Angew Chem Int Ed 43(3):369–373. doi:10.1002/anie.200352767 98. Mulder A, Onclin S, Pe´ter M, Hoogenboom JP, Beijleveld H, ter Maat J, Garcı´a-Parajo´ MF, Ravoo BJ, Huskens J, van Hulst NF, Reinhoudt DN (2005) Molecular printboards on silicon oxide: lithographic patterning of cyclodextrin monolayers with multivalent, fluorescent guest molecules. Small 1(2):242–253. doi:10.1002/smll.200400063 99. Bruinink CM, Nijhuis CA, Pe´ter M, Dordi B, Crespo-Biel O, Auletta T, Mulder A, Scho¨nherr H, Vancso GJ, Huskens J, Reinhoudt DN (2005) Supramolecular microcontact printing and dip-pen nanolithography on molecular printboards. Chem Eur J 11(13): 3988–3996. doi:10.1002/chem.200401138 100. Sadhu VB, Perl A, Pe´ter M, Rozkiewicz DI, Engbers G, Ravoo BJ, Reinhoudt DN, Huskens J (2007) Surface modification of elastomeric stamps for microcontact printing of polar inks. Langmuir 23(12):6850–6855. doi:10.1021/la063657s 101. Nijhuis CA, Yu F, Knoll W, Huskens J, Reinhoudt DN (2005) Multivalent dendrimers at molecular printboards: influence of dendrimer structure on binding strength and stoichiometry and their electrochemically induced desorption. Langmuir 21(17):7866–7876. doi:10. 1021/la051156l 102. Nijhuis CA, Sinha JK, Wittstock G, Huskens J, Ravoo BJ, Reinhoudt DN (2006) Controlling the supramolecular assembly of redox-active dendrimers at molecular printboards by scanning electrochemical microscopy. Langmuir 22(23):9770–9775. doi:10.1021/la0615894 103. Nijhuis CA, Boukamp BA, Ravoo BJ, Huskens J, Reinhoudt DN (2007) Electrochemistry of ferrocenyl dendrimer – β-cyclodextrin assemblies at the interface of an aqueous solution and a molecular printboard. J Phys Chem C 111(27):9799–9810. doi:10.1021/jp068853m 104. Nijhuis CA, Dolatowska KA, Ravoo BJ, Huskens J, Reinhoudt DN (2007) Redox-controlled interaction of biferrocenyl-terminated dendrimers with β-cyclodextrin molecular printboards. Chem Eur J 13(1):69–80. doi:10.1002/chem.200600777 105. Ling XY, Reinhoudt DN, Huskens J (2008) Reversible attachment of nanostructures at molecular printboards through supramolecular glue. Chem Mater 20(11):3574–3578. doi:10.1021/cm703597w 106. Yang L, Gomez-Casado A, Young JF, Nguyen HD, Cabanas-Dane´s J, Huskens J, Brunsveld L, Jonkheijm P (2012) Reversible and oriented immobilization of ferrocenemodified proteins. J Am Chem Soc 134(46):19199–19206. doi:10.1021/ja308450n 107. Ludden MJW, Mulder A, Tampe´ R, Reinhoudt DN, Huskens J (2007) Molecular printboards as a general platform for protein immobilization: a supramolecular solution to nonspecific adsorption. Angew Chem Int Ed 46(22):4104–4107. doi:10.1002/anie.200605104 108. Ludden MJW, Mulder A, Schulze K, Subramaniam V, Tampe´ R, Huskens J (2008) Anchoring of histidine-tagged proteins to molecular printboards: self-assembly, thermodynamic modeling, and patterning. Chem Eur J 14(7):2044–2051. doi:10.1002/chem.200701478 109. Ludden MJW, Huskens J (2007) Attachment of proteins to molecular printboards through orthogonal multivalent linkers. Biochem Soc Trans 35(3):492–494. doi:10.1042/BST0350492 110. Ludden MJW, Li X, Greve J, van Amerongen A, Escalante M, Subramaniam V, Reinhoudt DN, Huskens J (2008) Assembly of bionanostructures onto β-cyclodextrin molecular printboards for antibody recognition and lymphocyte cell counting. J Am Chem Soc 130(22):6964–6973. doi:10.1021/ja078109v 111. Ludden MJW, Ling XY, Gang T, Bula WP, Gardeniers HJGE, Reinhoudt DN, Huskens J (2008) Multivalent binding of small guest molecules and proteins to molecular printboards inside microchannels. Chem Eur J 14(1):136–142. doi:10.1002/chem.200701250 112. Ludden MJW, Sinha JK, Wittstock G, Reinhoudt DN, Huskens J (2008) Control over binding stoichiometry and specificity in the supramolecular immobilization of cytochrome c on a molecular printboard. Org Biomol Chem 6(9):1553–1557. doi:10.1039/B718940K

Cyclodextrin-Based Molecular Machines 113. Li J, Loh XJ (2008) Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery. Adv Drug Deliv Rev 60(9):1000–1017. doi:10. 1016/j.addr.2008.02.011 114. Yuen F, Tam KC (2010) Cyclodextrin-assisted assembly of stimuli-responsive polymers in aqueous media. Soft Matter 6(6):4613–4630. doi:10.1039/C0SM00043D 115. Zhou J, Ritter H (2010) Cyclodextrin functionalized polymers as drug delivery systems. Polym Chem 1(10):1552–1559. doi:10.1039/C0PY00219D 116. Moya-Ortega MD, Alvarez-Lorenzo C, Concheiro A, Loftsson T (2012) Cyclodextrin-based nanogels for pharmaceutical and biomedical applications. Int J Pharm 428(1–2):152–163. doi:10.1016/j.ijpharm.2012.02.038 117. Cotı´ KK, Belowich ME, Liong M, Ambrogio MW, Lau YA, Khatib HA, Zink JI, Khashab NM, Stoddart JF (2009) Mechanised nanoparticles for drug delivery. Nanoscale 1(1):16–39. doi:10. 1039/b9nr00162j 118. Lee J, Lee J, Kim S, C-j K, Lee S, Min B, Shin Y, Kim C (2011) Sugar-induced release of guests from silica nanocontainer with cyclodextrin gatekeepers. Bull Korean Chem Soc 32 (4):1357–1360. doi:10.5012/bkcs.2011.32.4.1357 119. Yang Y-W (2011) Towards biocompatible nanovalves based on mesoporous silica nanoparticles. MedChemComm 2(11):1033–1049. doi:10.1039/C1MD00158B 120. Park C, Oh K, Lee SC, Kim C (2007) Controlled release of guest molecules from mesoporous silica particles based on a pH-responsive polypseudorotaxane motif. Angew Chem Int Ed 46 (9):1455–1457. doi:10.1002/anie.200603404 121. Du L, Liao S, Khatib HA, Stoddart JF, Zink JI (2009) Controlled-access hollow mechanized silica nanocontainers. J Am Chem Soc 131(42):15136–15142. doi:10.1021/ja904982j 122. Meng H, Xue M, Xia T, Zhao Y-L, Tamanoi F, Stoddart JF, Zink JI, Nel AE (2010) Autonomous in vitro anticancer drug release from mesoporous silica nanoparticles by pH-sensitive nanovalves. J Am Chem Soc 132(36):12690–12697. doi:10.1021/ja104501a 123. Zhao Y-L, Li Z, Kabehie S, Botros YY, Stoddart JF, Zink JI (2010) pH-operated nanopistons on the surfaces of mesoporous silica nanoparticles. J Am Chem Soc 132(37):13016–13025. doi:10.1021/ja105371u 124. Chen T, Fu J (2012) An intelligent anticorrosion coating based on pH-responsive supramolecular nanocontainers. Nanotechnology 23(50):505705. doi:10.1088/0957-4484/23/50/ 505705 125. Patel K, Angelos S, Dichtel WR, Coskun A, Yang Y-W, Zink JI, Stoddart JF (2008) Enzymeresponsive snap-top covered silica nanocontainers. J Am Chem Soc 130(8):2382–2383. doi:10.1021/ja0772086 126. Park C, Kim H, Kim S, Kim C (2009) Enzyme responsive nanocontainers with cyclodextrin gatekeepers and synergistic effects in release of guests. J Am Chem Soc 131(46): 16614–16615. doi:10.1021/ja9061085 127. Guo W, Wang J, Lee S-J, Dong F, Park SS, Ha C-S (2010) A general pH-responsive supramolecular nanovalve based on mesoporous organosilica hollow nanospheres. Chem Eur J 16(29):8641–8646. doi:10.1002/chem.201000980 128. Kim H, Kim S, Park C, Lee H, Park HJ, Kim C (2010) Glutathione-induced intracellular release of guests from mesoporous silica nanocontainers with cyclodextrin gatekeepers. Adv Mater 22(38):4280–4283. doi:10.1002/adma.201001417 129. Silveira GQ, Vargas MD, Ronconi CM (2011) Nanoreservoir operated by ferrocenyl linker oxidation with molecular oxygen. J Mater Chem 21(16):6034–6039. doi:10.1039/ C0JM03738A 130. Lee J, Kim H, Kim S, Lee H, Kim J, Kim N, Park HJ, Choi EK, Lee JS, Kim C (2012) A multifunctional mesoporous nanocontainer with an iron oxide core and a cyclodextrin gatekeeper for an efficient theranostic platform. J Mater Chem 22(28):14061–14067. doi:10.1039/C2JM32137H

A. Hashidzume et al. 131. Park C, Lee K, Kim C (2009) Photoresponsive cyclodextrin-covered nanocontainers and their sol-gel transition induced by molecular recognition. Angew Chem Int Ed 48(7):1275–1278. doi:10.1002/anie.200803880 132. Ferris DP, Zhao Y-L, Khashab NM, Khatib HA, Stoddart JF, Zink JI (2009) Light-operated mechanized nanoparticles. J Am Chem Soc 131(5):1686–1688. doi:10.1021/ja807798g 133. Breslow R (1987) Artificial enzymes. Cold Spring Harbor Symp Quant Biol 52:75–81. doi:10.1101/SQB.1987.052.01.011 134. Breslow R (1995) Biomimetic chemistry and artificial enzymes: catalysis by design. Acc Chem Res 28(3):146–153. doi:10.1021/ar00051a008 135. Bjerre J, Rousseau C, Marinescu L, Bols M (2008) Artificial enzymes, “Chemzymes”: current state and perspectives. Appl Microbiol Biotechnol 81(1):1–11. doi:10.1007/s00253008-1653-5 136. Takashima Y, Osaki M, Harada A (2004) Cyclodextrin-initiated polymerization of cyclic esters in bulk: formation of polyester-tethered cyclodextrins. J Am Chem Soc 126 (42):13588–13589. doi:10.1021/ja047171e 137. Osaki M, Takashima Y, Yamaguchi H, Harada A (2007) Polymerization of lactones initiated by cyclodextrins: effects of cyclodextrins on the initiation and propagation reactions. Macromolecules 40(9):3154–3158. doi:10.1021/ma062650e 138. Harada A, Osaki M, Takashima Y, Yamaguchi H (2008) Ring-opening polymerization of cyclic esters by cyclodextrins. Acc Chem Res 41(9):1143–1152. doi:10.1021/ar800079v 139. Osaki M, Takashima Y, Yamaguchi H, Harada A (2007) An artificial molecular chaperone: poly-pseudo-rotaxane with an extensible axle. J Am Chem Soc 129(46):14452–14457. doi:10.1021/ja075140o 140. Takashima Y, Osaki M, Ishimaru Y, Yamaguchi H, Harada A (2011) Artificial molecular clamp: a novel device for synthetic polymerases. Angew Chem Int Ed 50(33):7524–7528. doi:10.1002/anie.201102834