Development of rotaxane type molecular ratchets M1 Ryo Takabayashi, Tobe laboratory Division of Frontier Materials Science, Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University 1

Contents -Introduction 1. Molecular Machine 2. Rotaxane 3. Molecular Ratchet -Examples of Molecular Ratchets 1. The First Paper 2. The Second Paper -Summary - My Approach toward a Molecular Ratchet 2

Molecular Machines What is a molecular machine A molecular machine is an assembly of a distinct number of molecular components that are designed to perform machinelike movements linked to a specific function as a result of an appropriate external stimulation. Molecular brake Rotaxane based Molecular elevator Balzani, V.; Credi, A. Angew. Chemie. 2000, 39, Molecular switch 3

Rotaxane A rotaxane is a supramolecule consisting of a ring component and a dumbbell- shaped axle component threaded through the ring. Bulky parts called stoppers at the terminal of the axle component prevent the ring component from slipping out. ＋ Ring Dumbbell shaped axle Features of a rotaxane ・ Station Most rotaxanes have stations on the axle component. The ring component is stabilized at the station due to interaction between components (e.g. hydrogen bonb). ・ Shuttling Shuttling is back-and-forth motion of the ring component between the stations along the axle. Shuttling Station 4

Rotaxane-based Simple Molecular Shuttle Simple molecular shuttle Tian, H.; Wang, Q. Chem. Soc. Rev. 2006, 35, 361–374. The position of the ring was changed due to different stability between components. ⇒ This process is governed by simple thermodynamics. 5

Sophisticated Molecular Shuttle Sophisticated molecular shuttle Unidirectional motion of the ring was achieved. ⇒ This step is similar to that of a ratchet. 6 Stoddart, J. F. et. al. J. Am. Chem. Soc. ASAP.

Molecular Ratchet Ratchet : A ratchet is a mechanical device that allows linear or rotary motion in only one direction while preventing motion in the opposite direction. Molecular Ratchet : Molecular machines possessing motions like that of ratchet are called molecular ratchets. A molecular ratchet has unidirectional movement. Definition Forward motion Backward motion To design and construct a molecular ratchet is difficult, so there are few reports on molecular ratchets. Research on molecular ratchets which provides new approaches in control of molecular machines has attracted much attention recently. 7

Face selective translation of a cyclodextrin ring along an axle Oshikiri, T.; Yamaguchi, H.; Takashima, Y.; Harada, A. Chem commun. 2009, 5515–

Previous work Axle component The one edge (the left one) is relatively bulky, and the other (the right one) is bulky enough to prevent the ring component from slipping. The ring component can thread the axle, and can slip from the left edge. Ring component  -Cyclodextrin (  -CD) The structure of  -Cyclodextrin is similar to that of a cone.  -Cyclodextrin has two faces; the primary face is smaller, the secondary face is larger. Oshikiri, T.; Takashima, Y. Eur. j. Org. Chem. 2007, 13, 7091– Pseudorotaxane A pseudorotaxane has no bulky stopper; slipping of the ring component can happen. Designed Pseuodrotaxane (a) Chemical Structure(b) 3D Structure Secondary face Primary face

Previous work Mixed in a 1 : 4 molar ratio in D 2 O at 343 K 0a 0b 0c 0d Face selective intrusion of the ring into the axle Correlation between time and degree of complex formation of  -CD with the axle component.  -CD on the 1st station (0a and 0c),  -CD on the 2nd station (0b and 0d) with different face directions. Oshikiri, T.; Takashima, Y. Eur. j. Org. Chem. 2007, 13, 7091– Easier

Approach to a Molecular Ratchet By combination of a relatively bulky spacer in the middle of an axle component and  -Cyclodextrin, a pseudorotaxane expected to have face selective transportation was designed. 11

Structure Axle component The one edge (the left one) is relatively bulky, and the other (the right one) is bulky enough to prevent the ring component from slipping. The ring component can thread the axle, and can slip from the left edge. A relatively bulky spacer is introduced in the middle of the axle. Ring component  -Cyclodextrin 12 Designed Pseudorotaxane (a) Chemical Structure Secondary face Primary face (b) 3D Structure

Experiment Mixed in a 1 : 4 molar ratio in D 2 O at 343 K These spectra show ・ The rate of the threading of  -CD into the axle component was much faster than that of the shuttling between the first alkyl station and the second alkyl station. ・ Complexes between the axle component and  -CD with different face directions on each station were formed. 1 H NMR spectra of (a)the axle without  - CD (b) soon after mixing with  -CD (c) 7 days after mixing at 343 K in D 2 O 13 The first alkyl stationThe second alkyl station

Experiment Mixed in a 1 : 4 molar ratio in D 2 O at 343 K Correlation between time and degree of complex formation of  -CD with the axle component.  -CD on the 1st station (1a and 1c),  -CD on the 2nd station (1b and 1d) with different face directions. 14

Result Kinetic parameters on the shuttling of  -CD (a) between 1a and 1b (b) between 1c and 1d, and then (c) comparison of rate constants on the translation of  -CD in 1a to 1b, and 1c to 1d. 15

Conclusions ・ The translation of  -CD on the psuedorotaxane was kinetically controlled by the well-designed spacer. ・ This behavior should be derived from the difference between the transition states of the translations; the activation energy barrier in the case where the wider side of  -CD faces to the second station of the axle is much lower than that of the opposite direction. ・ This is the first observation that a ring is transferred between two stations on an axle molecule with face selectivity. 16

Quantitative Active Transport in [2]Rotaxane Using a One-Shot Acylation Reaction toward the Linear Molecular Motor Makita, Y.; Kihara, N.; Takata, T. J. Org. Chem. 2008, 9245–

Motivation Since unidirectional movement is entropically unfavored (  S < 0), the supply of free energy is necessary to realize such movement. To make a molecular motor possessing an unidirectional transport system, it is necessary thermodynamically unfavored change induced by a certain free energy source. Schematic representation of a [2]rotaxane-based linear molecular motor and its periodic potential surface. 18

Approach to a Molecular Ratchet Concept of unidirectional transposition of the ring component in the rotaxane. (a) The ring component is trapped at the ammonium station, so dethreading is prevented. (b) By neutralization of the ammonium group, the ring component is released from the station. Due to the bulky end-cap, the ring component tentatively migrates to the center of the axle component. (c) Before the nonselective slipping of the axle component, a bulky acyl group is introduced on the amino group to prevent dethreading beyond the nitrogen. × trapped This reaction is very rapid 19

Preliminary Experiment Rotaxane 1 was synthesized to conduct a preliminary experiment. Features of the rotaxane ・ An asymmetric axle component possessing one station ・ One stopper (the left one) is relatively bulky, but the ring component can pass on it, and the other (the right one) is bulky enough to prevent the ring component from dethreading. ・ 1 was stable in CD 3 CN (no dethreading). ・ The reaction from 2 to 4 or from 2 to 5 + DB24C8 (the ring component) was very rapid (checked by 1 HNMR). 20 Dethreading

Result of Preliminary Experiment a Initial concentration of 1 was 15 mM. The reactions were carried out at r.t. for 15 min in CD 3 CN in the presence of 5.0 equivalent of Et 3 N. b Determined by the 1 H NMR spectra of the crude product (isolated yield given in parentheses). c [4]/([4] + [6]) d The reaction was carried out for 24 h. e Not detected. These data show DMAP accelerated the acylation reaction. These data show the more bulky stopper in the left side prevented the ring from dethreading more efficiently. These data show the rotaxane formation of 1c by acylation with all three reagents worked very well. ・ The simple first order kinetics (  1/2 = 462 h at 333 K in CD 3 CN) from 1c to 5c. ⇒ The dethreading of 1c to form 5c is a thermodynamically favored process in the presence of triethylamine. ・ 1d was stable under the presence of triethylamine (no dethreading). ⇒ The ring component in 2c dethreaded the axle component not beyond the 3,5-dimethylphenyl end-cap but beyond the neopentyl-type end-cap. 21

Crystal Structures of 1b and 4cr Crystal structure of 1b and 4cr (a) 1b. Hydrogens and PF 6 - were omitted for clarity. (b) 4cr. Hydrogens were omitted for clarity. 22

Summary about Preliminary Experiment ・ The migration of the ring component toward the proximate end-cap is thermodynamically favored movement for 1c during the treatment with triethylamine. However, in the acylation experiments, the ring in 1c migrated toward a thermodynamically unfavored direction to produce 4cr quantitatively. The movement is unidirectional transport, which was achieved by the local potential surface on the axle of 1c and 2c. ・ The effect of the neopentyl-type group as the distant end-cap was examined; The ring can pass over the neopentyl-type end cap, but the dethreading was relatively prevented because of the bulkiness. 23

Experiment and Result stable at 333 K in DMSO Rotaxane 7 was synthesized to conduct a main experiment. Features ・ An asymmetric axle component possessing one station ・ One stopper (the right one) is relatively bulky, but the ring component can pass on that, and the other (the left one) is bulky enough to prevent the ring component from dethreading. With the interaction between the axle component and the ring component, the neopentyl group acts as the sufficiently bulky end-cap to prevent dethreading (in 7). However, without the intercomponent interaction, the neopentyl-type group behaves as the sufficiently small end-cap to allow the dethreading of the ring component (in 9). The unidirectional transport of the ring was successful. × trapped Dethreading of 8 occurred rapidly at 333 K in CD 3 CN to form 9 and DB24C8 (  1/2 = 1.2 h) in the absence of triethylamine. 24 BzCl neopentyl

Conclusions ・ The direction of transport is influenced by the local potential surface and not by the thermodynamic stability. In other words, it is driven by the gradient of the local potential surface and the free energy due to acylation and not as a result of attractive interactions. ・ These features are essential parts of chemical energy-driven unidirectional linear molecular motors. ・ The present work demonstrates that imitation of natural molecular motors can be realized in simple molecular systems by a simple reaction that utilizes the local potential surface. 25

Future Work ・ An artificial linear molecular motor system can be envisioned to be a simple extension of the transport system, and that was under construction. (a) to (b): The Boc group is deprotected, and the ring component migrates to the thermodynamically stable ammonium station. (b) to (c): The ammonium groups are acylated by Boc group, and the ring component unidirectionally migrates to the space between the Boc and the neopentyl groups. (c) to (d): The selective deprotection of the TFA group is followed by application of protonation forces to the ring component in order to move it to the thermodynamically stable ammonium salt station. (d) to (e): The ammonium group is acylated by TFAA, and the ring component unidirectionally migrates to the space between the TFA and the neopentyl groups. 26

Summary 27 ・ Molecular ratchet are molecular machines possessing motions like that of ratchet are called molecular ratchets. A molecular ratchet has unidirectional movement. ・ Two molecular machines, which can be called molecular ratchets, are introduced in this presentation. In the first paper, a ring was transferred between two stations on an axle molecule with face selectivity. In the second paper, unidirectional transportation of a ring on an axle molecule was achieved by a well-designed local potential surface.

My Approach toward a Molecular Ratchet 28

Process of My Dynamic Potential Change System Dynamic potential change system 29

Structure of Target Molecular Ratchet 30

以下質問対策 31

Molecular Ratchets A definition of ratcheting in chemical terms Research on rotaxanes possessing ratcheting systems, so called molecular ratchets, has been interested in recently. “Ratcheting” is the capturing of a positional displacement of a substrate through the imposition of a kinetic energy barrier which prevents the displacement being reversed when the thermodynamic driving force is removed. The key feature of ratcheting is that the ratcheted part of the system is not linked with (i.e., not allowed to exchange the substrate with) any part of the system that it is ratcheted from. Ratcheting is a crucial requirement for allowing a Brownian machine to be reset without undoing the task it has performed. Because it is used to kinetically stabilize an ultimately thermodynamically unfavorable state, ratcheting is intrinsically associated with a sequential logic sequence applied to a Brownian substrate. J. AM. CHEM. SOC. 9 VOL. 128, NO. 12, 2006 Ratcheting means controlling relative motions between components kinetically to an thermodynamically unfavorable states. In other words 32

Application of Rotaxane to Molecular Machines Sophisticated molecular switch (ratio) stimulus The probability of the ring changed virtually. This process is not governed by simple thermodynamics. This can be explained with a ratchet system. shuttling Serreli, V.; Lee, C.-F.; Kay, E. R.; Leigh, D. A. Nature 2007, 445 (7127), Virtually no change after stimulus 33

Rotaxane-based Simple Molecular Shuttle Simple molecular shuttle Tian, H.; Wang, Q.-C. Chem. Soc. Rev. 2006, 35, 361−374. stimulus1stimulus2 This process is governed by simple thermodynamics 34

Synthesis (i) a. n-BuLi, diethylamine, THF, 195 K, 1 h; b. 1,8-dibromooctane, THF, 195 K to 323 K, overnight, 35%. (ii) 1-(10-Iodo-decyl)-3,5- dimethylpyridinium iodide, acetone, reflux, 4 d, 93%. (iii) Methyl iodide, acetone, r.t., 3 d, 15%. 35

Rotaxane Synthesis 36

Supplementary explanations Pseudrotaxane A pseudrotaxane has no bulky stopper; slipping of a ring component can happen. The structure of  -Cyclodextrin similar to that of a cone.  -Cyclodextrin has two faces; the primary face is smaller, the secondary face is larger.  -Cyclodextrin 37

Preliminary Experiment (2) a Initial concentration of 1 was 15 mM. The reactions were carried out at r.t. for 15 min in CD 3 CN in the presence of 5.0 equivalent of Et 3 N. b Determined by the 1 H NMR spectra of the crude product (isolated yield given in parentheses). c [4]/([4] + [6]) d The reaction was carried out for 24 h. e Not detected. 38