University of Groningen Control of translational and rotational movement at nanoscale Stacko, Peter

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Control of translational and rotational movement at nanoscale

Stacko, Peter

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Control of Translational and

Rotational Movement at Nanoscale

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The research described in this thesis was carried out at the Stratingh Institute for Chemistry, University of Groningen, Netherlands.

The work was financially supported by NanoNextNL of the Government of the Netherlands and 130 partners.

Printed by Ipskamp Printing BV, Enschede, The Netherlands. The cover image is used under Creative Commons CC0 license. ISBN: 978-94-034-0203-1

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Control of Translational and

Rotational Movement at

Nanoscale

PhD Thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Friday 17 November 2017 at 16:15

by

Peter Štacko

born on 26 August 1987

in Bojnice, Slovak Republic

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Supervisors

Prof. B. L. Feringa

Prof. W. R. Browne

Assessment Committee

Prof. N. H. Katsonis

Prof. R. C. Chiechi

Prof. R. J. M. Nolte

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Chapter I:

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Introduction

On a daily basis, whether we realize it or not, we are fortunate to witness the impressive collection of molecular machines and devices developed by Nature to operate complex biological processes responsible for various functions in our organisms.1_{The level of efficiency and selectivity achieved at the molecular level}

in these systems is nothing short of spectacular and staggering. In analogy to the macroscopic machines and the motor engines that drive them, biological molecular motors represent a fundamental basis for operating the molecular machines in the cell by virtue of converting chemical or thermal energy to generate forces and motion required to perform an array of functions.2_A

notorious example of this would be the ATP synthase containing molecular motor to control the process of synthesis or hydrolysis of ATP.3_{Other examples}

comprise of flagella motor responsible for movement of bacteria4,5_{, motors}

involved in muscle contractions and other various protein-based motors6_.

Complementing the level of sophistication and elegance contained within the design of these systems, they constitute a major source of inspiration for the scientists attempting to develop synthetic molecular machinery. Since directly employing these systems ex vivo is possible7,8_{but difficult due to their inherent}

instability outside biological conditions, considerable effort to develop simpler systems capable of tolerating a wider range of conditions has been made. The growth of synthetic chemistry over the decades enabled nearly limitless construction of systems that both mimic and extend beyond the natural systems. This has led to design and assembly of synthetic machinery and nanostructures based on artificial molecular motors capable of harnessing of molecular motion to achieve many distinct functions.9–17_{Impressiveness of these achievements cannot}

be underestimated, especially when one takes Brownian motion into equation. Brownian motion is responsible for random motion and rotation of components at molecular level at temperatures above 0 K, thus rendering it to be the relentless enemy of controlled molecular motion.18_{Due to this, controlled molecular motion}

remains one of major challenges in contemporary chemistry.

Initially, several notable examples of biological motors provided by Nature and their further application in nanotechnology shall by briefly discussed, because understanding of the modus operandi of these systems is imperative for design of artificial molecular nanomachines and their further enhancement. The rest of

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the chapter shall examine a number of examples in which molecular motion was exploited to achieve a variety of functions in dynamic and controlled fashion.

Biological rotary motors

F

0

F

1

-ATP synthase

The motor protein found in mitochondria, bacteria and chloroplasts consists of two subunits F0 and F1 linked by a central axis (Figure 1). In principle, F0 is a

proton pump embedded in a membrane and the proton transport through F0

driven by a proton gradient drives unidirectional rotation of the central axle connecting F0 and F1. This movement results in conformational changes of F1

responsible for the formation of ATP. Interestingly, the process can be reversed to convert energy from ATP hydrolysis into a rotary motion to produce a proton gradient.19–23_{The enzyme is capable of hydrolyzing 390 molecules of ATP per}

second which translates into 130 rotations of axle per second. This is rather remarkable for a system of such high complexity and efficiency capable of converting chemical energy to mechanical energy and ultimately energy storage in the form of ATP.24,25

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Bacterial flagella motors

Many bacteria require motility for their growth and survival. While other types of motility exist, flagellum-mediated translational motion is the most common mechanism.26–31_{Flagellar motion is driven by flux of protons or sodium cations}

across the cytoplasmic membrane (Figure 2). In general, the directional rotary motion of the flagella results in bundling of the helical flagella and propulsion of the cell through the environment. This motion can also be reversed or the flagellar filaments separate resulting in random motion with little translational movement (tumbling).32

Figure 2. Bacterial flagellar motor.

Applications of biological motors

The efficiency and reliability of biological motors have prompted also their application in artificial systems and conditions. Both rotary motors as well as linear-motion motors based on kinesin33_{, myosin and actin were exploited for this}

purpose.34–36

One demonstration of such application is a construction of nickel nanopropeller that rotates through the action of an engineered F1-ATPase motor (Figure 3a).37

The device was assembled by genetic engineering of histidine tags that stuck the F1-ATPase onto nickel posts with the stalk protruding upwards. This then

connected to a nickel propeller of ~1 μm length through biotin-streptavidin bonds. The rotation was initiated using 2mM adenosine triphosphate achieving ~1-8 rps and could be inhibited by sodium azide. A metal-binding site was also

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engineered into the motor to act as an on-off switch upon binding of zinc ion, reminiscent of putting a stick between two cogwheels.38

In a different instance, a hybrid device has been reported where gliding bacteria

Mycoplasma mobile was used to power a cogwheel-shaped silicon dioxide rotor of

20-μm diameter rotating inside a silicon track (Figure 3b). The motor fueled by glucose rotated at ~2 rpm and inherited some of the properties normally attributed to living systems.39

Figure 3. (a) An F1-ATPase–powered nanopropeller. (b) A microrotor (20-μm diameter)

powered by bacteria that adhere to the rotor and glide unidirectionally through the track. (reproduced from ref. 33)

An artificial organelle capable of producing ATP by coupled reactions between bacteriorhodopsin, a light-driven transmembrane proton pump, and F0F1-ATP

synthase motor protein, reconstituted in polymersomes has also been realized.40

While certainly impressive in many aspects, natural motors suffer from drawbacks such as limited lifetime ex vivo and poor tolerance of conditions outside of their natural environment. It is therefore desirable to explore and develop artificial molecular machines using bottom-up organic chemistry to address these issues.

Artificial molecular motors

Taking inspiration from Nature, a lot of emphasis has been made in the past decades on engineering and constructing artificial systems capable of performing various tasks. The advantages of artificial systems include increased stability under wide range of conditions and possibility to carefully tailor the design for

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the desired application. On the other hand, the control, directionality and interface to the outside world are yet far less developed than for the natural systems.

A series of different molecular systems capable of controlled molecular motion will be discussed in this section, including rotaxane and catenane based systems, chemically driven motors and finally photochemically driven molecular motors including some of their applications.

Rotaxane and catenane based molecular motors

In rotaxanes and catenanes, the arrangement of individual molecular components makes use of non-covalent mechanical interactions rather than covalent bonds. If the molecule consists of two interlocked macrocycles, it is called catenane, whereas in the rotaxane a marocycle is threaded by a linear axle. These systems have been pioneered by group of Sauvage and Stoddart and represent attractive foundation for development of molecular systems due to well-developed methods for their synthesis and ease with which they can be tailored for the specific application.13,16,41–44

Introducing additional control elements to catenanes allows for construction of unidirectional rotary motor (Figure 4).45_{In this instance, the ring preferentially}

resides on one or other of the two binding sites (stations), represented by the colored cylinders (orange and blue/green). The colored spheres (violet and red) are bulky groups which sterically block one of the two tracks between the stations. The blue-to-green and green-to-blue transformations result in a change of the binding affinity of a station for the small ring, providing a driving force for the ring to redistribute itself between the stations. When a red or purple sphere (linking reaction) is removed, the ring is allowed to move between stations by a particular route. Reattachment of the sphere (unlinking reaction) ensures a net directional rotation of the small ring.

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Figure 4. (a) Schematic representation of a unidirectional rotary cycle in catenane system.

(b) Potential energy surface for the small light blue ring. (reproduced from ref. 44)

Such rotary motor based on catenane scaffold has been demonstrated by Leigh and co-workers (Scheme 1).45_{The large ring contains two recognition sites for the}

smaller ring (cyan) – succinamide (yellow) and photoisomerizable fumaramide (purple). Triphenylmethyl (red) and silyl (magenta) groups can be selectively detached/reattached and serve as two bulky stoppers that control directionality of the movement. At the start of the cycle (Scheme 5, state I), the small ring is positioned at the fumaramide site. Irradiation (λ = 254 nm) generates maleamide moiety (green, state II) by photochemical isomerization of the fumaramide site. The silyl stopper is then removed which results in movement of the smaller ring in a clockwise fashion in order to bind to a more preferred succinamide site (state III), followed by a re-silylation. Backwards isomerization of the maleamide unit to the fumaramide unit in the presence of piperidine (IV) followed by de-tritylation/re-tritylation results in completing the second half of the cycle, returning the small ring back to the original site (state I). In overall, a 360° clockwise rotation of the small ring around the track is thus achieved.

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Scheme 1. Unidirectional motor based on a catenane. (reproduced from ref. 44)

It should be noted that the system is operated by four orthogonal stimuli – three chemical transformations and a photochemical isomerization. The directionality is therefore not autonomous, i.e. inherent property of the system, but rather introduced by the sequence of the input, with the chemist playing the “hand of God”. While elegant in design, there are certain limitations rendering the approach somewhat unpractical, such as the time necessary to complete the reactions required to convert the system from one state to the other state.

This idea was further expanded and exploited to synthesize peptides in a sequence specific manner inspired by ribosomes found in Nature (Scheme 2).46

The design is based on a rotaxane containing a macrocycle with a reactive arm and a thread-axle decorated with amino acids. The macrocyle moves along the axis in a manner reminiscent of the ribosome units moving along the mRNA strand. The reactive arm detaches each amino acid from the axle, passing it to the end of the residue, resulting in elongation of the specific sequence. The sequence and spacing of the amino acids tethered to the axle allows for a sequence specific peptide synthesis analogous to the mRNA template in cells. In comparison to

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Nature’s ribosome, the system is much less efficient, however, it demonstrates the ability to incorporate controlled molecular motion in complex systems and further harnessing it to achieve a more advanced function.

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In another example by the Stoddart group, rotaxane based molecular system has been shown to perform work by bending cantilever beams using redox chemistry.47_{First, a monolayer of bistable redox-active [3]rotaxane molecules}

self-assembled on an array of microcantilever beams was prepared (Figure 5a). Exposure to chemical oxidants and reductants was used to drive switching of the rotaxane from its stretched to the contracted form (and vice versa) resulting in controllable and reversible bending of the cantilevers (Figure 5c-d). While challenges, such as the development of direct electrical or optical stimulation, remain, this example serves as a good foundation for the production of a class of multiscale nanomechanical devices based upon molecular mechanical motion.

Figure 5. (a) Molecular structures of the rotaxanes used in the device. (b) UV-Vis absorption

spectrum of both extended (green) and contracted (blue) [3]rotaxanes. (c) Schematic diagram of the proposed mechanism of the device’s operation. (d) Bending of the four cantilever beams as the aqueous oxidant (Ox) and reductant (Red) are introduced into the system. (reproduced from ref. 46)

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Chemically driven molecular motors

The first attempt for a chemically driven unidirectional motor has been reported by Kelly et. al (Scheme 3).48_{The system consisting of a triptycene connected to a}

helicene was capable of performing a controlled unidirectional 120° rotation through five consecutive steps. In the first step, the amino group (1.1) is converted into an isocyanate 1.2 by addition of phosgene. Rotation around the central bond brings the isocyanate group to the vicinity of the hydroxyl group attached to the trptycene and a subsequent intramolecular cyclization results in a formation of a urethane linker. At this point, the molecule is trapped in undesirable strained conformation 1.4 and the helicene therefore moves around the triptycene part to afford the more stable conformation 1.5. Rotation in the other direction is prevented by the urethane linker. Finally, the urethane is cleaved and a rotamer

1.6 of the starting atropoisomer 1.1 is generated by a 120° rotation around the

central axis. Despite numerous structural modifications of the system and a lot of exerted effort, a successful molecular motor capable of repetitive 360° rotations was not developed.49

Scheme 3. Depiction of chemically driven 120° rotation of motor 1.1. (reproduced from ref.

47)

However, in the group of Feringa, a chemically driven molecular motor capable of 360° rotation in a repetitive fashion was successfully developed.50_{The motor}

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four distinct stations of the rotary cycle (Scheme 4). In stations A and C, the rotation around the biaryl bond is locked due to the presence of lactone, whereas in stations B and D the rotation is retarded by steric hindrance in the tetrasubstituted biaryl. Unidirectionality of the motion is achieved in steps 1 and 3 by enantioselective reduction of the lactone resulting in asymmetric ring opening, followed by orthogonal deprotection/protection of the phenol in steps 2 and 4. Since a specific sequence of chemical reagents is required to operate the process, the system cannot be considered autonomous. Therefore, like in other non-autonomous systems only a very low frequency of rotation is accessible due to each chemical step requiring certain time for completion. On the other hand, inversion of the rotary direction can be easily achieved by using the other enantiomer of the chiral reagent in step 1 and 3 together with different order of protection and deprotection of the phenol in steps 2 and 4.

Scheme 4. (left) The rotary cycle for the chemical driven rotary motor; (right) Schematic

illustration for the operation of unidirectional motor, viewed from top. A rotor (yellow and blue) is driven, about an axis, in the clockwise direction relative to the position of a stator (red). (reproduced from ref. 49)

One of the most recent examples of chemically driven molecular motors exploits a palladium redox cycle to power directional rotation around a single bond in an axially chiral biaryl moiety (Scheme 5).51_{The cycle starts with an enantiomerically}

pure atropoisomer of the sulfoxide (S,M)-1.2 undergoing a C-H activation using palladium acetate to form the palladacycle Pd[(R,P)-1.2]XL. In this instance, the sulfoxide acts as a directing group and the resulting palladacycle possesses greatly reduced barrier to atropoisomerization, facilitating interconversion of Pd[(R,P)-1.2]XL to 1.2]XL. Subsequently, the Pd-C bond in

Pd[(R,M)-1.2]XL is transformed to C-H bond to complete unidirectional 180° rotation. The

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the C-Br bond using Pd2dba3 and PCy3 to provide the palladacycle Pd[(R,P)-1.2]BrL. Again, the biaryl axis becomes conformationally labile due to presence of

a cyclic linker, thus lowering the barrier for atropoisomerization. Reintroducing the C-Br bond using NBS completes the full unidirectional 360° rotation.

Scheme 5. (left) The rotary cycle for the rotary motor 1.2 based on a palladium redox cycle.

The blue rotor rotates through 360° in a clockwise sense with respect to the red stator. Four steps responsible for the rotation: (i) C-H activation; (ii) reintroduction of C-H bond; (iii) oxidative addition; (iv) reintroduction of C-Br bond (reproduced from ref. 50)

Photochemically driven molecular motors

Unidirectional molecular motors constitute a unique group of photoresponsive molecules capable of converting light energy into unidirectional rotary motion. These overcrowded alkenes consist of two relatively bulky halves connected with a double bond and one or two stereogenic centers responsible for the inherent and autonomous directionality. Due to steric hindrance around the double bond, planarity is disrupted and the molecule adopts a twisted and helical conformation.52,53

In 1999, the group of Feringa reported an example of first generation molecular motor. This generation features two identical halves connected with a double bond and one stereogenic center in each half (Figure 6).54_{These molecules are}

generally synthesized employing a McMurry protocol using zinc powder and TiCl4 or TiCl3.

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Figure 6. Examples of first generation molecular motors.

In 2002, a second generation of molecular motors was introduced. The two halves connected by the central double bond were no longer identical and the number of stereogenic centers was reduced from one to two (Figure 7).55_{Due to use of two}

different building block, the McMurry reaction was no longer very suitable for their preparation and thus a new strategy had to be developed. The molecules are generally prepared by a Barton-Kellogg coupling of a thioketone and a diazo-functionalized building block with subsequent desulphurization using a phosphine.56

Figure 7. Examples of second generation molecular motors.

The rotary cycle

The full 360° unidirectional cycle occurs through a four-stage switching cycle consisting of two photochemically driven E-Z isomerizations and two thermal isomerizations (Scheme 6). The two photochemical isomerizations represent two energetically uphill steps requiring energy in form of light to overcome the barrier. The thermal helix inversion steps are irreversible and downhill in energy, which is crucial to the directionality of the motor (vide infra).

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Scheme 6. Four-step rotary cycle of a second generation motor 1.3.

In the first step, irradiation of stable (M)-trans 1.3 leads to a photochemical isomerization of the double bond to form unstable (P)-cis 1.3 (Scheme 6, step 1). The irradiation is a reversible process and continuous irradiation eventually leads to a photostationary state (PSS) where the ratio of the two compounds remains constant. This ratio strongly depends on the respective absorption spectra of the two isomers as well as quantum yield for both forward and backward isomerization. Throughout the process, the initially pseudo-axially oriented methyl group at the stereogenic center is forced to adopt an unfavorable pseudo-equatorial orientation which results in a sterical clash of the methyl with lower half. The sterical strain imposed on the molecule is thus released in the subsequent thermal helix inversion of unstable (P)-cis 1.3 to stable (M)-cis 1.3 where the upper half slips past the lower half and the pseudo-equatorially oriented methyl is allowed to adopt a pseudo-axial orientation again (Scheme 6, step 2). In both of these steps the helicity of the alkene is switched from M to P and from P to M, respectively and a net 180° rotation of the upper half with respect to the lower half is achieved, representing a half of the rotary cycle. Another photoinduced

E-Z isomerization (Scheme 6) followed by a thermal helix inversion (Scheme 6)

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Effect of structural modifications on rate of the rotation

It has been found that the rate of photochemical step is in the order picoseconds57,58_{and therefore generally much faster than the rate of thermal}

isomerization. To this end, the thermal helix isomerization is considered to be the rate determining step in the rotary cycle.59,60_{A considerable library of motors}

based on different scaffolds and bearing various substituents has been synthesized and studied in order to understand the structural-kinetic relationship (Figure 8, vide infra).

As has been discussed beforehand, in the process of thermal helix inversion, the upper half of the motor passes around the lower half and therefore it is not surprising that the rate of this process is strongly dependent on the steric hindrance between these two halves (fjord region).

Figure 8. Representative collection of molecular motors and their rotation rates given as

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For example, one of the first second generation motors consisting of a six-membered upper and lower halves rings (1.6) exhibits half-life of the thermal process in order of hours.55_{Increasing the steric hindrance by using a}

seven-membered lower half (1.8) decreases the rate by over one order of magnitude.61,62

Introducing even more rigid lower half built from a five-membered ring (1.4) that is not capable of bending during the thermal isomerization process to accommodate the slippage, the half-life is increased to order of hundreds to thousands of years.63_{On the other hand, when the upper half in this molecule is}

substituted for a five-membered ring56,64,65_{(1.7), a rather fast motor with a}

half-life of minutes is generated. This half-half-life can be decreased even further to miliseconds or nanoseconds if a flexible six-membered ring (1.5) is introduced in the lower half66_{or a sterically bulky t-butyl group (1.10) is installed at the}

stereogenic center67_{, respectively. Decrease of the barrier in the latter case is}

caused presumably due to destabilization of the ground state by a large substituent compared to the regular methyl substituted motor.

Functional light-driven molecular motors and machines

Control over position of functional groups and helicity

As described previously, both first and second generation molecular motors undergo photochemically driven cis-trans/E-Z isomerizations as part of the four-step rotary cycle. One of the consequences of the isomerization is a large geometrical change that can be further exploited to exert a function or position of functional groups located on the two halves of the molecular motor. At the same time, the thermal helix inversion from the metastable state back to the stable state of the motor is accompanied with an inversion of intrinsic helicity of the overcrowded alkene. Both of these properties have been heavily exploited in our group, since especially the inversion of helicity, together with the ability to continuously rotate under irradiation, are the hallmarks of molecular motors that separate them from other switches.

First generation motors have been applied in a photochemical control of intramolecular aggregation of perylenebisimide decorated molecular motor.68

The same principle was applied for study of interaction of radicals in a TEMPO-substituted molecular motor. In the trans-state, the EPR spectrum shows no interaction due to a large distance between the two groups, whereas in the cis state a strong coupling signal is observed.69_{In these two examples, the molecular}

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motor was used as a two-stage switch, controlling distance between the two moieties.

In order to utilize the inversion of helicity, a photoswitchable organocatalyst 1.11 has been developed (Figure 9).70_{The motor 1.11 features a DMAP as a}

nucleophilic site and a base on one half of the molecule and a thiourea moiety capable of hydrogen bonding to a substrate on the other half of the molecular motor. In the cis-state, the two groups are located in close proximity allowing enantioselective catalysis of 1,4-addition of thiophenol to cyclohexanone. Since the helicity of the overcrowded alkene 1.11 the in untastable cis-state and stable

cis-state is opposite, essentially two pseudoenantiomers of the same

organocatalyst are accessible in one molecule. The motor 1.11 was shown to catalyze a Michael addition and either of the two enantiomers of the product could be obtained in very good enantiomeric excess depending on which state of the motor was used. When the trans-isomer was used, only racemic product was slowly formed (loss of cooperativity).

Figure 9. (left) The organocatalyst 1.11 based on a light-driven molecular motor and a

schematic representation of helicity inversion; (right) Chiral HPLC traces of the reaction product using the trans-isomer (I), metastable cis-isomer (II), stable cis-isomer (III). (reproduced from ref. 69)

Exercising control over chirality of the overcrowded alkene has been also exploited in a dynamic control of helicity of isocyanate polymer. The polymerization was initiated with an optically active motor 1.12 (Figure 10).71_The

polymer terminated with an E-isomer did not show any preference for formation of either M- or P-helical polymer. Photoinduced isomerization to the cis-isomer resulted in an exclusive formation of the M-helical polymer. The following

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thermal helix inversion to Z-stable led to generation of the opposite P-helical polymer due to a change in folding of the dynamic polymer. This case clearly demonstrates capability of the motor to transfer the chirality onto appending moieties in a dynamic fashion.

Figure 10. Schematic illustration of dynamic control over the helicity of a polymer by a

photochemically active molecular motor. (reproduced from ref. 70)

Control of directional motion

Another prominent feature of the motors is to exhibit continuous directional rotary motion often accompanied with a large geometrical change. Recently, this fact has been exploited in a transfer of a cargo from one site to another one (Scheme 7).72_{The system was based on a second generation molecular motor}

bearing a phenol and amine moieties. In the starting state, the acetyl located on the phenol (site A) was picked up by a sulfide (site B) to form a thioacetate. Photochemical isomerization of the double bond transferred the acetyl from the vicinity of the phenol to the other side of the molecule where it was picked up by benzylamine (site C). Thus, the cargo could be displaced using non-invasive stimuli by roughly 2 nm.

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Scheme 7. Proposed operation mode for acetyl transfer from A to C. (reproduced from ref.

71)

In a different example, the group of Tour employed the ability of motors to perform continuous unidirectional rotary movement to create submersible nanomachines (Figure 11).73_{A series of molecular motors and switches with}

attached fluorophores was prepared and their diffusion coefficients were studied at both ambient conditions and under irradiation with UV-light. The rate of diffusion was found to strongly correlate with the type of motor or switch that was used. Irradiation of a control molecule (B) did not lead to an increase in diffusion coefficient, while that of a slow molecular motor showed marginal increase (C). In case of the fast molecular motor (A), an increase of 26% in the diffusion rate was measured which was in turn larger than for the non-directional equivalent switch (D, 10%). This example demonstrates that light-controlled and continuous directional movement of single molecules can manifest itself in a form of macroscopically measurable property such as diffusion rate.

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Figure 11. A series of submersible nanomachines A-D and the change in diffusion

coefficient of A and D upon UV-irradiation. (reproduced from ref. 72)

Perhaps the most prominent example of achieving directional movement is the nanocar reported by the group of Feringa (Figure 12).74_{The molecule 1.13}

consisted of chassis connected to four unidirectional rotary motors. The motors are capable of undergoing continuous rotary motion and therefore act as molecular wheels similar to the wheels of a car. The nanocar was deposited on a copper surface and visualized using UHV-STM. In this case, the excitation of the molecule was achieved using STM tip instead of irradiation with UV-light. Using this method, the molecule was shown to move across the surface utilizing paddlewheel-like movement and several consecutive isomerizations resulted in a preferentially directional movement across the surface, showing that the directional rotary motion of single motor units can be translated into translational motion (Figure 13).

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Figure 12. (a) The structure of nanocar 1.13 with embedded four molecular motors acting

as wheels. (b) Schematic representation of the concept (Figure reproduced from ref. 73)

Figure 13. (a) STM image (imaging parameters: area 10.2 nm × 39.3 nm, current I = 74 pA,

U = 47 mV) of the initial position. The black area was scanned only after the molecule moved into it. (b) Trajectory depicting the individual steps taken. (c) Final position after ten consecutive voltage pulses. (d) The action spectrum for movement shows a voltage threshold at 500 mV. Each data point represents 8 to 40 manipulations performed on various molecules (I = 30–50 pA). Error bars represent the standard deviation from the probability for successful events. (e) STM frames corresponding to individual steps of the trajectory in (b) excluding starting and final position (reproduced from ref. 73).

However, directional movement and transport is not limited only to molecular or microscopic scale. Doping a liquid crystalline (LC) environment with a single enantiomer of a second generation motors results in a light-responsive cholesteric phase (Figure 14).75–77_{Photoinduced switching of the motor helicity is amplified}

by the LC layer which changes its helical organization. The motion of the LC layer has been used to rotate microscale particles and glass rods thus demonstrating that molecular motors are capable of producing work. Irradiation of the motor

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1.14 embedded in the LC layer results in a clockwise rotation of a glass rod on top

of this film (Figure 14). The rotation of the rod is terminated when the photostationary state is reached and thermal relaxation of the unstable state of the motor 1.14 then results in the rotation of the object in the opposite direction.

Figure 14. (a) Molecular motor 1.14 used to dope a liquid-crystal (LC) film. (b) Cholesteric

phase of the LC film doped with the molecule 1.14. (c) Rotation of a glass rod placed on top of the LC film upon irradiation with UV-light; frames taken at 15 s intervals. (d) Surface of the liquid-crystal film as imaged using atomic force microscopy (AFM). (reproduced from ref. 75)

Molecular motors in materials

A possibility to apply molecular motors for application of molecular motors in functional materials has been explored in the literature as well. In the group of Feringa, molecular motors have been anchored to surfaces in order to control its properties (e.g. wettability).78_{Using an altitudinal motor 1.15 bearing a lipophilic}

perfluoroalkyl group grafted onto a surface, the water contact angle could be controlled by irradiation with UV-light. In the cis-isomer, the water contact angle of 60° was measured since the more lipophilic perfluoroalkyl chain was not exposed to the outside of the surface. Upon switching to the trans-isomer, exposure of the perfluoroalkyl chain resulted in a more lipophilic surface,

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increasing the water contact angle to 80°. Alternative systems employing dipodal79–81_{and tetrapodal}82_{mode of attachment utilizing both covalent}83_and

non-covalent84_{interactions with the surface have also been demonstrated.}

Figure 15. (top) Perfluoroalkyl functionalized molecular motor grafted on a surface.

(bottom left) Water droplet on stable cis-1.15 SAM. (bottom right) Water droplet on stable trans-1.15 SAM. (reproduced from ref. 77)

A different, highly elegant approach to responsive functional materials has been shown by group of Giusepponi.85_{In this instance, a network of}

oligoethylene-linked second generation molecular motors was constructed using copper catalyzed “click” chemistry between azide and terminal acetylene (Figure 16). The resulting gel was shown to contract and eventually collapse upon photochemical actuation due to amplification of twisting and winding of the polymer chains by unidirectionally rotating molecular motors. It should be noted that the incoming light causes the system to operate far-from-equilibrium and this could potentially lead to integration of nanomachines in metastable materials to store and convert energy.

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Figure 16. (a) Polymer network featuring a second generation motor. (b) Visualization of

macroscopic gel deformation upon irradiation with UV-light. (c) Change in relative volume of the gel based on length of irradiation. (reproduced from ref. 84)

Conclusions and outline of the thesis

The previous sections address both biological motors as well as artificial molecular motors starting with rotaxane and catenane based systems, followed by chemically and photochemically driven molecular motors, operating in solution, on surfaces and in functional materials. In some examples, amplification of this controlled movement can translate into physical work performed at micro and nanoscale.

While undeniable progress in the field of molecular motors has been made, major room for further improvement and novel applications still remains. The chapters in this thesis seek to apply light-driven molecular motors and switches to

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advanced functional systems eventually capable of performing controlled mechanical work, especially aiming at more complex rotational movement (Chapter 5), linear translational movement on surfaces (Chapter 2 and 4) and interesting responsive amphiphile-based materials (Chapter 6).

Chapter 2 focuses on the design and synthesis of photoresponsive molecular dragsters based on a simplified design of molecular nanocar reported by our group previously. The behavior upon irradiation with UV-light in solution is examined by UV-vis and 1_{H NMR spectroscopy. Preliminary results of AFM and}

STM experiments under ambient conditions are also reported.

Chapter 3 reports preparation of first examples of molecular motors featuring quaternary stereogenic motor substituted with fluorine motivated by the desire for higher photochemical and electrochemical stability. The influence of such substitution on photochemistry and the respective thermal helix inversion is investigated using UV-vis, 1_{H and}19_{F NMR spectroscopy.}

Chapter 4 explores a possibility of omitting a stereogenic center from the structure of molecular motors while retaining autonomous unidirectionality in the photochemically driven rotary cycle. The synthetic knowledge regarding fluorinated motors obtained in chapter 3 has been successfully applied in synthesis of several third generation molecular motors. Their photochemical and thermal behavior was examined using UV-vis, 1_{H and}19_{F NMR spectroscopy.}

In chapter 5, molecular motor scaffold incorporating a biaryl moiety for a purpose of tidally locked rotation of the naphthyl residue around the alkene moiety is demonstrated. This more complex coupled movement is investigated and proven using UV-vis, CD and 1_{H NMR spectroscopy.}

Chapter 6 describes the preparation of a family of amphiphile derivatives based on the bisthioxanthylidene core. The ability of these derivatives featuring various lipophilic chains and hydrophilic head groups to self-assemble in water is examined using cryo-TEM microscopy. Applications of these amphiphiles for the purpose of osmotic loading of micelles, photochemically driven control of surface tension and amplification of chirality in nanotubes, is also discussed.

Chapter 7 focuses on the design and preparation of second generation molecular motors with appending long and rigid arms. Influence of the arm length on dynamics in the excited state and thermal helix inversion is investigated using

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UV-vis and ultrafast fluorescence spectroscopy in collaboration with the group of prof. Meech.

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Chapter II:

Molecular dragsters: Towards controlled

translational motion on surfaces

Molecular dragsters bearing two appending molecular motor units as the propelling wheels have been synthesized. The two dragsters feature different sizes of the rotor units. The motors preserve their rotary function in solution and preliminary experiments regarding movement on a surface under ambient conditions have been performed.

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Introduction

Directional motion of molecules offers prospects for development of unique and unprecedented nanotechnology devices rivaling machinery developed by Nature1,2_{such as motor proteins moving along microtubules}3_{, the ATPase rotary}

motion4,5_{or myosin V walking on actin filaments}6,7_{. Examples of directional}

motion in the literature include DNA walkers8,9_{, photochemically}10,11_and

redox-driven12_{motors and catenane, and rotaxane translational systems, although the}

systems are predominantly studied in solution.13–17

Regarding surface confined motors, directional movement can be divided to rotary or translational motion. Achieving rotary motion is the more straightforward option as the two major conditions to be fulfilled are anchoring the molecules on the surface18–22_{and the surface should not interfere with}

process of controlling the motion; such as quenching of the excited state for photochemically driven molecules, or redox reaction between the molecules and surface for electrochemically driven processes.

On the other hand, there are many obstacles associated with autonomous directional translational movement on surfaces. For example, the attractive forces between the molecules and the surface have to be strong enough to facilitate physisorption of molecules on the surface, while at the same time, the forces have to be weak enough to allow for propulsion along the surface upon application of stimuli. Perhaps due to the delicate balance necessary to achieve this goal, autonomous directional movement of molecules on surface constitutes a major challenge in contemporary chemistry.

Though, several examples of directional translational movement of molecules; such as fullerenes23_{, porphyrins}24_{, cyclodextrins}25_{or molecular landers}26_{, on}

surfaces can be found in the literature, however, the majority of them is induced by “pushing” or “pulling” of the molecules with an STM tip (e.g. non-autonomous).27,28_{In addition, most of the observed motion is attributed to}

sliding or slipping motion, rather than rolling motion and the exceptions to these observations will be discussed here.

In a simple example, Grill et. al. have demonstrated that a molecule consisting of two triptycene units connected with an axle (Figure 1a) can exhibit translational movement when adsorbed on a Cu (110) surface at 25 K.28_{Placing the STM tip}

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on top of the molecule and moving it perpendicular to the axle of the molecules, 4 nm translational movement was observed (Figure 1b-d).

Figure 1. (a) Two triptycene units connected with an axle. (b) Scheme of manipulation

with the STM tip. (c) STM image of the molecule on Cu (110) prior to manipulation. d) STM image of the molecule after the manipulation. (reproduced from ref. 24)

The group of Tour was able to demonstrate the wheel-assisted rolling motion on gold surface at single molecular level using STM.29–31_{For this purpose, the}

nanocar 2.1 with four wheels as well as the three-wheel analogue 2.1 has been synthesized (Figure 2). The comparison of movement for the two molecules provided the evidence for wheel-assisted rolling motion. Upon heating the Au surface to 200 °C only the four-wheel nanocar 2.1 showed translational motion perpendicular to the axes, whereas the analogue 2.1 displayed pivoting motion (Figure 3). This behavior demonstrates the expected fullerene-facilitated rolling which is contrast to most examples in the literature where simple pushing is almost universally accepted as the mechanism for large molecules.32–34

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Figure 2. The structure of nanocar 2.1 (left) and the three-wheel analogue 2.2 (right);

(Figure reproduced from ref. 25) In addition, both pushing and pulling movement induced by the STM tip was examined on these molecules. Slightly curved, however preferentially linear movement was clearly observed (Figure 3). This movement could not be reproduced when the tip was positioned on the side of the molecule instead of behind the molecules.

Figure 3. (left) Nanocar 2.1 rolling on Au surface. (a-e). A small section of a sequence of

images taken during annealing at ~200 °C (Vb = -0.95 V, It = 200 pA; image size is 51 × 23

nm2_{). The orientation of 2.1 is determined easily by the fullerene wheel separation, with}

motion occurring perpendicular to the axles. The acquisition time for each image is

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approximately 1 min, with a-e selected from a series spanning 10 min, which shows 80° pivot (a) followed by translation interrupted by small-angle pivot perturbations (b-e). (right) Structure and pivot motion of the trimers. (a) Structure of trimers. A sequence of STM images (b-e) acquired approximately 1 min apart during annealing at ~225 °C show the pivoting motion of 2.2 (both circled molecules) and lack of translation in b-e of any molecules. (Vb = -0.7 V, It ) 200 pA; image size is 34 × 27 nm2). Monatomic step edges in

these images are lined with clustered molecules. (f) A summary of the two methods of motion for the different structures showing that nanocar 2.1 consecutively pivots and then translates perpendicular to its axles, whereas trimer 2.2 pivots but does not translate on the surface. For clarity, both structures are drawn devoid of the alkoxy units (reproduced from ref. 27).

Another attempt from group of Tour and co-workers to construct a “motorized nanocar”, rather than a car being pushed or pulled by STM tip contained

p-carborane as a wheel and a light-driven molecular motor as the engine of the

nanocar 2.3.35,36_{The molecule was thought to be propelled by the molecular}

motor along the substrate surface as it can perform repetitive unidirectional rotary motion induced by light (Figure 4). The molecule has only been studied by 1_{H NMR and UV-vis spectroscopy in the solution and unfortunately, no}

reports of movement on surface studied by STM have been made. The function of the molecular motor was preserved in the presence of p-carborane units unlike in the case of fullerene-C60 wheels.29

Figure 4. (left) The structure of the nanocar 2.3 with p-carborane units as wheels and

molecular motor in the middle. (right) Irradiation (a) of the motor unit leads to rotation of the motor (b) inducing the forward translational motion (c-d). (Reproduced from ref. 25)

Perhaps the most successful demonstration of unidirectional movement on a surface has been reported by the group of Feringa.37_{The molecular nanocar 2.4}

features a chassis connected to four molecular motors designated to propel the molecule along the surface when performing the rotational movement (Figure

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46 |

5). Upon electronic excitation using an STM tip double bond isomerization occurs followed by a helix inversion resulting in rotary motion pushing the molecule forward. A correct configuration of the stereogenic centers was required as only in the meso isomer both of the motor units rotate in the forward direction from the external point of view. Ultimately, the molecule was shown to undergo a preferentially linear movement showing that the intrinsic motor function is capable of converting external energy input into mechanical action (Figure 6).

Figure 5. (a) The structure of nanocar 2.4 with embedded four molecular motors as

wheels. (b) Schematic representation of the concept (Figure reproduced from ref. 33)

Figure 6. (a) STM image (imaging parameters: area 10.2 nm × 39.3 nm, current I = 74 pA,

U = 47 mV) of the initial position. The black area was scanned only after the molecule moved into it. (b) Trajectory depicting the individual steps taken. (c) Final position after ten consecutive voltage pulses. (d) The action spectrum for movement shows a voltage threshold at 500 mV. Each data point represents 8 to 40 manipulations performed on various molecules (I = 30–50 pA). Error bars represent the standard deviation from the probability for successful events. (e) STM frames corresponding to individual steps of the trajectory in (b) excluding starting and final position (reproduced from ref. 33).

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Design of the dragsters

Some of the initial difficulties in the molecular nanocar project included poor volatility of the molecule for surface deposition as well as rather high voltage required for movement of the molecule. Motivated by the success of the electrically-driven molecular nanocar, we sought to address these issues by simplifying the design along with enabling modification of the molecule for future applications such as cargo transport. One could imagine a cargo unit being attached to the motorized part and once at the desired destination, the cargo could be released. For this purpose, we envisioned that molecular dragsters bearing only two rotating motor units (instead of four) could be sufficient (Figure 7). To first prove that the unidirectionality of the molecular dragsters on surface is preserved, only a dummy cargo unit, sharing the same carbazole building block as the other half of the molecule, was attached at this point. In order to assess the influence of wheel “size” on the unidirectional movement, we decided to construct two dragsters with different wheel sizes – one based on simple fluorene units and the second one, larger, based on phenyl substituted fluorene units.

Figure 7. The design of the molecular dragsters consisting of a motorized part with two

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Synthesis of the dragsters and intermediates

Due to similarities in the design, the synthesis of the molecular dragsters is based on that of the molecular nanocar 2.4, although with several crucial modifications in both synthetic and purification procedures.37

The synthesis started with the preparation of 2,7-dibromo-9H-carbazole as it is a common building block for both parts of the molecule (2.11 and 2.18a-b, vide

infra). For this purpose, 4,4’-dibromobiphenyl was nitrated using fuming nitric

acid in glacial acetic acid (Scheme 1).38,39_{The resulting mono-nitrated product} 2.7 was then subjected to reductive cyclization using PPh3 in o-DCB at high

temperature to facilitate the formation of 2.8 in a good overall yield.40

Scheme 1. Synthesis of 2.8 as the common intermediate for further synthesis.

From this intermediate, both parts of the dragster have been synthesized. The carbazole 2.8 was reacted with a large excess (4 eq.) of 1,4-diiodobenzene in Ullmann coupling catalyzed by CuI and 1,10-phenanthroline as a ligand to provide the N-substituted carbazole 2.9 (Scheme 2).41_{The excess of}

1,4-iodobenzene prevented the formation of the di-substituted product as well as Ullmann coupling between two molecules of the starting material.

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Scheme 2. Synthesis of the unpropelled part 2.11 of the dragsters from the carbazole 2.8.

Following a procedure for Sonogashira coupling with TMSA using Pd(PPh3)Cl2

and CuI as the catalysts, a TMS-protected acetylene was installed onto the molecule to give compound 2.10. The acetylene would then, upon deprotection, serve as a connection point with the other half of the molecule. It should be stressed that excess of TMSA was avoided as it led to coupling at the bromo-substituted positions even at room temperature. Besides that, a complete selectivity for the iodo-substituted reaction site was observed. Metal-halogen exchange at -78 °C using n-BuLi, followed by a substitution of the di-lithiated carbazole with TMSCl and deprotection of the acetylene in situ with KOH afforded the final building block 2.11 in 84 % yield over the three steps (Scheme 3).

In the next stage, the motorized part 2.18a-b of the dragster was to be synthesized. Unlike in the case of the nanocar 2.4 where the solubilizing hexyl chains were introduced via Sonogashira coupling followed by hydrogenation37_,

in this synthesis the alkyl moieties were installed in one step using Pd(dppf)Cl2

University of Groningen Control of translational and rotational movement at nanoscale Stacko, Peter

Control of translational and rotational movement at nanoscale

Stacko, Peter

Control of Translational and

Rotational Movement at Nanoscale

Control of Translational and

Rotational Movement at

Nanoscale

PhD Thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Friday 17 November 2017 at 16:15

by

Peter Štacko

born on 26 August 1987

in Bojnice, Slovak Republic

Supervisors

Prof. B. L. Feringa

Prof. W. R. Browne

Assessment Committee

Prof. N. H. Katsonis

Prof. R. C. Chiechi

Prof. R. J. M. Nolte

Table of Contents

| 9

Chapter I:

10

|

Introduction

| 11

Biological rotary motors

F

F

-ATP synthase

12

|

Bacterial flagella motors

Applications of biological motors

| 13

Artificial molecular motors

14

|

Rotaxane and catenane based molecular motors

| 15

16

|

| 17

18

|

| 19

20

|

Chemically driven molecular motors

| 21

22

|

Photochemically driven molecular motors

| 23

The rotary cycle

24

|

| 25

Effect of structural modifications on rate of the rotation

26

|

Functional light-driven molecular motors and machines

Control over position of functional groups and helicity

| 27

28

|

Control of directional motion

| 29

30

|

| 31