domain: chim phys

text:
Seifallah Abid

Guillaume Erbland

Claire Kammerer

Gwénaël Rapenne

Prototypes of molecular gears with an organometallic piano-stool architecture

Keywords:

In the field of Molecular Machines, molecular gears have mainly been synthesized to be studied in solution. Then, the cogwheel subunits are restricted to be only arranged in an intramolecular manner. In the last years, the possibility to arrange a train of gears at the single molecular level and observe the propagation of a rotation motion from one molecule to its neighbor using Scanning Tunneling Microscopy (STM) opened new perspectives with the opportunity to have intermolecular arrangements on surfaces. In this chapter, we describe the research background of single molecular gears and our strategy using organometallic piano-stool complexes to anchor such gears on surfaces. Our molecules incorporate two subunits linked together through a ruthenium center acting as a ball bearing. The lower part is the anchoring tripodal ligand and the upper part the cogwheel. Various functionalities have been explored to behave as teeth, ranging from mono-dimensional phenyl rings to bidimensional porphyrin fragments.

Introduction

Molecular Machines

A revolution in the way chemists consider molecular systems and their associated motions took place over the last decades with the rise of a new field dedicated to Molecular Machines. Macromolecular biological systems acting as machines have been long optimized by Nature and are key elements to many functions in living organisms. However, in artificial molecular systems, the design and synthesis of molecular machines for which motion and function can be controlled remains a highly challenging task. In this context, Jean-Pierre Sauvage, Sir Fraser Stoddart and Ben Feringa were awarded the 2016 Nobel Prize of Chemistry for their seminal and fundamental contributions to this field [START_REF] Sauvage | From chemical topology to molecular machines (Nobel Lecture)[END_REF][START_REF] Stoddart | Mechanically interlocked molecules (MIMs)-molecular shuttles, switches, and machines (Nobel Lecture)[END_REF][START_REF] Feringa | The art of building small: From molecular switches to motors (Nobel Lecture)[END_REF].

A large variety of artificial molecular machines and motors have been developed in a monumentalization approach, starting with small molecular building blocks and building step by step a complexified architecture until the molecule becomes a machine. In particular, daily life macroscopic objects have been miniaturized according to a technomimetic approach [4] leading to nanometer scale syringes [START_REF] Ikeda | Molecular design of a "molecular syringe" mimic for metal cations using a 1,3-alternate calix[END_REF], wheels [START_REF] Joachim | Molecule concept nanocars: Chassis, wheels, and motors?[END_REF][START_REF] Chu | Synthesis and single-molecule imaging of highly mobile adamantane-wheeled nanocars[END_REF][START_REF] Jacquot De Rouville | Synthesis and STM imaging of symmetric and dissymmetric ethynyl-bridged dimers of boron-subphthalocyanine bowl-shaped nano-wheels[END_REF][START_REF] Nickel | STM Manipulation of boron-subphthalocyanine nano-wheel dimers on Au(111)[END_REF], wheelbarrows [START_REF] Jimenez-Bueno | Technomimetic molecules: synthesis of a molecular wheelbarrow[END_REF][START_REF] Rapenne | Molecular machines: Synthesis and characterization of two prototypes of molecular wheelbarrows[END_REF][START_REF] Grill | Imaging of a molecular wheelbarrow by scanning tunneling microscopy[END_REF], vehicles [START_REF] Shirai | Directional control in thermally driven single-molecule nanocars[END_REF][START_REF] Vives | Synthesis of single-molecule nanocars[END_REF][START_REF] Jacquot De Rouville | Synthesis of polycyclic aromatic hydrocarbon-based nanovehicles equipped with triptycene wheels[END_REF][START_REF] Kudernac | Electrically driven directional motion of a four-wheeled molecule on a metal surface[END_REF][START_REF] Rapenne | World's first nanocar race: a single molecule piloted per team[END_REF], scissors [START_REF] Muraoka | Light-driven open-close motion of chiral molecular scissors[END_REF], elevators [START_REF] Badjić | A molecular elevator[END_REF], gyroscopes [START_REF] Khuong | Rotational dynamics in a crystalline molecular gyroscope by variable-temperature 13 C NMR, 2 H NMR, X-ray diffraction, and force field calculations[END_REF], motors [START_REF] Kelly | Unidirectional rotary motion in a molecular system[END_REF][START_REF] Koumura | Light-driven monodirectional molecular motor[END_REF][START_REF] Ruangsupapichat | Reversing the direction in a light-driven rotary molecular motor[END_REF][START_REF] Hernandez | A reversible synthetic rotary molecular motor[END_REF][START_REF] Kassem | Artificial molecular motors[END_REF][START_REF] Jian | En route to surface-bound electric field-driven molecular motors[END_REF][START_REF] Garcia-Lopez | Light-activated organic molecular motors and their applications[END_REF][START_REF] Vives | Prototypes of molecular motors based on star-shaped organometallic ruthenium complexes[END_REF][START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF][START_REF] Tierney | Experimental demonstration of a single-molecule electric motor[END_REF][START_REF] Baroncini | Photo-and redox-driven artificial molecular motors[END_REF][START_REF] Zhang | A chiral molecular propeller designed for unidirectional rotations on a surface[END_REF] among others.

In spite of the tremendous developments witnessed in this field, applications of ultimately miniaturized machines in the macroscopic world are still rare. One of the strategies to exploit such nanoscale units is to deposit them on surface and use them as self-assembled monolayers or single molecules thanks to the amazing capabilities offered by Scanning Tunneling Microscopy (STM). Beyond the high-resolution imaging possibilities, the use of the STM tip can allow to induce and control precise molecular motions from the single molecular scale [START_REF] Grill | Rolling a single molecular wheel at the atomic scale[END_REF] to the switch of large domains [START_REF] Zhang | Simultaneous and coordinated rotational switching of all molecular rotors in a network[END_REF].

In this context, one fascinating target is a train of molecular gears rotating synchronously on a surface to be able to transfer energy at the nanoscale from a molecule to another one over long distances.

Gears in the Insects' World

The oldest known machine involving gearing mechanisms is the Antikythera machine, built around 200 BC. However, in contradiction with the common idea that gears are a human invention, micrometric gears were recently discovered in the nymphs of the planthopper Issus coleoptratus [START_REF] Burrows | Interacting gears synchronize propulsive leg movements in a jumping insect[END_REF]. Indeed, the exoskeleton of their hind legs incorporates a curved strip with up to 12 micrometric gear teeth, as observed by Scanning Electron Microscopy (Figure 1). Both legs are thus mechanically coupled through this gearing mechanism, leading to a synchronized motion from the preparation to the propulsion of the jump, that can reach 2 m. Interestingly, it must be noted that the dissymmetric character of the teeth allows only one direction of powered rotation.

According to this recent discovery, synthesis of molecular gears can be defined not only as technomimetic [4] but also as biomimetic [START_REF] Breslow | Biomimetic chemistry: biology as an inspiration[END_REF].

Molecular Gears from Solution to Surface

Gears in Solution: Drawbacks and Limitations

The first examples of synthetic molecular gears appeared forty years ago as intramolecular systems involving two intertwined subunits undergoing correlated motion in solution. The two pioneers in this field, H. Iwamura [START_REF] Kawada | Unconventional synthesis and conformational flexibility of bis(1-triptycyl)ether[END_REF] and K. Mislow [START_REF] Hounshell | Stereochemical consequences of dynamic gearing in substituted bis(9-triptycyl)methanes and related molecules[END_REF], first reported compounds exhibiting bevel-gear mechanisms, with two triptycene moieties linked by a very short spacer such as a methylene group in the case of Mislow (Figure 2, left) or an oxygen atom in the case of Iwamura (Figure 2, center). The first molecular spur gears with two triptycene units having parallel axes of rotation (Figure 2, right) were designed and synthesized in 2012 by J. Siegel, a former PhD student of K. Mislow, with a particular attention paid to the inter-axle distance as key parameter in molecular gearing mechanisms [START_REF] Frantz | Molecular spur gears comprising triptycene rotators and bibenzimidazole-based stators[END_REF]. In the last years, M. Shionoya reported a new series of molecular gears which can be controlled at will by an external stimulus. These complexes are based on platinum(II) with two azaphosphatriptycene ligands acting as cogwheels. Under thermal or photo-activation, cis-trans isomerization of the complex leads very elegantly to the engagement or disengagement of the cogwheels (Figure 3) [START_REF] Ube | Metal-centred azaphosphatriptycene gear with a photo-and thermally driven mechanical switching function based on coordination isomerism[END_REF]. A vast majority of the studies on correlated motion, such as the ones presented above, have been performed in solution, at the intramolecular level. The observed behavior is thus the average behavior of an assembly of molecules and not of a single molecule. Moreover, the lack of orientation in solution prevents transfer of motions (i.e. energy) over long distances, which is a limitation for applications. As an alternative, intermolecular gearing becomes possible on a supporting surface, which enables to maintain the distance between cogwheels and the relative orientation of the axles.

Gears on Surface: Single Molecules and Atomic Resolution

Intermolecular gearing on a surface was evidenced for the first time in 2007 by Moresco et al. in a rack and pinion device made of penta(p-tert-butylphenyl)-(p-tert-butylpyrimido)benzene molecules on a Cu(111) substrate (Figure [START_REF] Chiaravalloti | A rack-and-pinion device at the molecular scale[END_REF]. Indeed, STM lateral manipulation of one single molecule along the edge of the close-packed island obtained after on-surface deposition resulted in a rotary motion of this per-arylated benzene pinion, as a consequence of the teeth intertwining. This rotation was demonstrated by comparing successive STM images and following the trajectory of the chemically-tagged pyrimidine tooth. The same gear prototype was further investigated on Au(111) as a single molecule. When mounted on an atomic defect, the controlled and stepwise rotation of this per-arylated benzene molecule was successfully achieved [START_REF] Manzano | Step-by-step rotation of a molecule-gear mounted on an atomic-scale axis[END_REF], thus opening the way for intermolecular gearing on surface at the single molecular scale.

O H 2 C N N N N 4)
Unfortunately, when a second molecule was added in close vicinity to form a train of two gears, no correlated motion could be observed due to diffusion of the cogwheels. This underlines the prime importance of rotation axles to anchor cogwheels on surface at optimized intermolecular distances, as a prerequisite to favor transmission of rotary motion over diffusion.

A promising strategy to build intermolecular gearing systems consists in mounting molecular cogwheels on top of single atoms deposited on surface. This has been recently demonstrated by Joachim et al., who successfully mounted by STM lateral manipulation the per-arylated benzene cogwheel depicted in Figure 4 on top of a Cu single atom on a Pb(111) surface. In the presence of this centered rotational axle, controlled rotation of single cogwheels and correlated motion within a train of two gears was achieved [START_REF] Soe | Train of Single Molecule-Gears[END_REF].

Our Strategy

As an alternative, we envisioned to pre-assemble the cogwheel on top of a single atom axle in the frame of a coordination complex, synthesized in solution and subsequently deposited on surface. The architecture of our previously-reported ruthenium-based motor [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF] appeared particularly promising, since it has been shown that such structures can be displaced and arranged in a very precise assembly through STM lateral manipulation at 77 K, while diffusion is frozen at 5 K. This would thus enable the specific arrangement of trains of organometallic gears with finely tuned intermolecular distances at 77 K and would prevent gears disengagement due to diffusion by lowering the temperature to 5 K. Indeed, at that temperature, the motion of such ruthenium complexes is efficiently restricted by the strong interaction between the surface and the tripodal scorpionate ligand [START_REF] Kammerer | Scorpionate hydrotris(indazolyl)borate ligands as tripodal platform for surface-mounted molecular motors and gears[END_REF], which not only prevents translation but also gives a very efficient control on the geometry of the whole architecture thanks to the presence of three anchoring points. This rigid tripodal ligand also holds a second key function as it supports the ruthenium ion, acting as single atom axle for the star-shaped cogwheel. The structure of the cogwheel should be as rigid as possible with few degrees of freedom in order to obtain a maximum control over the mechanically-driven motion. Indeed, in these experiments, the STM tip will be used as a source of mechanical energy to induce the rotary motion of the first cogwheel, that will be mechanically transmitted to the next one if gearing mechanism is effective (Figure 5). The propagation of rotary motion within the train of gears will then be evidenced by comparing the STM images of the initial and final states. As we will see later, it will be helpful to have one of the teeth chemically or sterically tagged. In this chapter we will focus on the design and molecular synthesis of cogwheel prototypes to build a train of gears based on star-shaped organometallic ruthenium complexes.

Molecular Gears Based on Organometallic Ruthenium Complexes

Design

As mentioned above, our design for molecular gears including a rotational axle is based on the previouslyreported ruthenium-based motor [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF] shown Figure 6 (left). The lower part of gears is a tripodal thioether-functionalized hydrotris(indazolyl)borate ligand to anchor molecules on metallic surfaces, but also to alleviate the ruthenium rotational axle and thus the upper cogwheel. A pentaphenylcyclopentadienyl moiety is used in this case as a central platform to modularly attach various peripheral groups acting as teeth. We explored two types of architectures, which are schematically presented in Figure 6 (center and right): the first architecture integrates five mono-dimensional arms and the second one five bi-dimensional paddles.

Efficient Synthesis of the Ruthenium Complex Precursor

From a synthetic point of view, both architectures of molecular gears featuring five identical mono-or bi-dimensional teeth stem from the same precursor via five-fold cross-coupling reactions. The key intermediate in this

STM tip Fe Fe Fe Me N N N N B H N N Ru SEt EtS EtS Fe N N N N B H N N Ru SEt EtS EtS N N N N B H N N Ru SEt EtS EtS
strategy is thus a ruthenium(II) complex bearing the tripodal scorpionate ligand on one side and a penta(p-bromophenyl)cyclopentadienyl ligand on the other side (Scheme 1). Owing to the importance of this building block for the synthesis of ruthenium-based rotary molecular machines, its synthesis was recently optimized [START_REF] Erbland | Expedient synthesis of thioether-functionalized hydrotris(indazolyl) borate as an anchoring platform for rotary molecular machines[END_REF]. It is now prepared in a reproducible manner in 5 steps and 31% overall yield on the longest linear sequence, compared to 8 steps formerly with a maximum yield of 4%.

3-Amino-4-methylbenzoic acid was first protected as an ethyl ester under standard conditions, and the o-toluidine moiety was next converted into an indazole scaffold using the modified one-pot Jacobson procedure with isoamylnitrite as nitrosating agent.

Step economy was achieved at that stage in this optimized route thanks to a highly efficient one-pot "N-deprotection / ester reductive sulfidation" sequence mediated by indium(III), allowing the direct conversion of N-acetyl indazolyl ester into the corresponding N-deprotected indazolyl thioether in a single step (instead of three). The reaction proceeds in the presence of indium(III) iodide as Lewis acid, an excess of 1,1,3,3-tetramethyldisiloxane as reducing agent and ethanethiol as nucleophile. Importantly, this one-pot sequence not only shortens the synthetic route towards the key ruthenium complex but also avoids the troublesome isolation of intermediates.

The next major improvement in the synthetic sequence relies on the replacement of potassium by thallium during the formation of the tripodal ligand. Indeed, the thallium salt of the tris(indazolyl)borate ligand was obtained via a thermally-controlled reaction of indazolyl thioether with potassium borohydride in the presence of thallium sulfate, leading to a highly pure crystalline product. Finally, the ruthenium(II) key precursor resulted from a ligand exchange on the bromidodicarbonyl-1,2,3,4,5-penta(p-bromophenyl)cyclopentadienyl ruthenium(II) complex, with a positive effect of microwave irradiation on this reaction.

Scheme 1: Optimized synthetic route yielding the ruthenium key precursor coordinated to the tripodal ligand (lower side) and a pentabrominated functionalized cyclopentadiene (upper side).

Molecular Gears Based on Cogwheels with mono-Dimensional Arms

With an optimized and shortened access to this ruthenium complex precursor, the synthesis of molecular gear prototypes has been pursued and cogwheels with mono-dimensional teeth were first targeted. In this family, the cyclopentadienyl ring is thus surrounded with five 4,4'-biphenyl moieties, each carrying one or two methyl or tertbutyl substituents on the outer positions (Figure 7). The synthesis of these three prototypes relies on a five-fold Suzuki-Miyaura cross-coupling reaction of the penta(p-bromophenyl)cyclopentadienyl ruthenium(II) key precursor in the presence of an excess of the appropriate boronic acid derivative [START_REF] Erbland | Star-shaped ruthenium complexes as prototypes of molecular gears[END_REF]. Using Pd(OAc)2 / SPhos as catalytic system and potassium phosphate as base in anhydrous toluene, the penta-substituted gear prototypes were obtained in 52 to 82% yield. These optimized conditions thus allow an efficiency as high as 88 to 96% for each single C-C bond formation. Full characterization of each complex confirmed the C5-symmetric character of the upper cogwheel. According to preliminary studies, such gear prototypes seem to be ineffective in propagating rotary motion to their neighbors. Theoretical calculations performed on intricated gears revealed that upon rotation of the first cogwheel, a vertical deformation of the teeth can occur, thus preventing the transfer of rotation to the next molecule.

To shut down this deformation pathway, the design of gear prototypes was adapted with 2D-paddles (Figure 6, right) instead of 1D-teeth (Figure 6, center). The very large steric hindrance of the groups surrounding the cyclopentadienyl core in this second generation of cogwheels is expected to prevent gear slippage. Indeed, according to the size and rigidity of these paddles, it seems impossible to rotate the first gear without rotating its neighbor provided the intermolecular distance is appropriate, and mechanical transmission of motion should thus be favored with this new design.

Molecular Gears Based on Cogwheels with bi-Dimensional Paddles

Three different chemical fragments exhibiting flat structures and large areas were selected as bi-dimensional paddles for this second generation of cogwheels. Four gear prototypes incorporating carbazoles, BODIPYs and porphyrins as paddles and exhibiting increasing diameters up to 5.2 nm were thus synthesized [START_REF] Erbland | Star-shaped ruthenium complexes as prototypes of molecular gears[END_REF]. Their chemical structures are shown in Figure 8, and one can notice that bulky alkyl groups have systematically been added to paddles to increase the solubility during the synthesis and above all, to avoid -stacking between neighboring molecules on surface, as this could hamper the gears motion. The four gear prototypes bearing 2D-paddles were prepared via a five-fold cross-coupling reactions applied to the appropriate brominated or iodinated penta(p-halogenophenyl)cyclopentadienyl ruthenium(II) key precursor. By way of example, a five-fold copper-catalyzed N-arylation reaction in the presence of 3,6-di-tert-butyl-9Hcarbazole afforded the pentacarbazole gear (Scheme 8, top right). Starting from penta(p-bromophenyl)cyclopentadienyl ruthenium(II) precursor, the target compound was obtained in 19% yield under optimized conditions involving copper iodide and ()-trans-cyclohexane-1,2-diamine as catalytic system in combination with potassium phosphate as base in refluxing 1,4-dioxane. Interestingly, when the same reaction conditions were applied to the more reactive iodinated precursor (same ruthenium complex with 5 iodine atoms instead of five bromines), the yield could be increased to 28%, corresponding to 78% per C-N coupling.

BODIPY fragments were next selected to vary the nature of the paddles and enlarge the cogwheel diameter. The standard Suzuki-Miyaura conditions used previously for the preparation of gears with 1D-arms failed to efficiently deliver the desired penta-substituted product, leading to mixture of compounds resulting from one to five C-C couplings. After optimization, it appeared that higher coupling efficiency could be reached in a ternary solvent system combining toluene, ethanol and water (2:2:1), and the penta-BODIPY gear prototype was obtained in 36% yield.

Finally, the largest paddle scaffold relied on a nickel porphyrin macrocycle featuring 3,5-di-tert-butylphenyl groups on three meso positions to enhance stability as well as solubility and limit -stacking. Metallation of the porphyrin moieties with nickel(II) was meant to prevent any undesired metallation on surface during STM studies, owing to the robustness of nickel porphyrins.

As a strategy to modulate the diameter of the cogwheel, it was envisioned to vary the length of the spacer between the cyclopentadienyl and tetrapyrrole cores. Starting from penta(p-halogenophenyl)cyclopentadienyl ruthenium(II) key precursor, a Suzuki-Miyaura coupling would deliver a biphenyl spacer whereas a Sonogashira reaction would provide a longer phenylethynylphenyl linker. The required A3B-type porphyrin precursors incorporating a phenylboronic ester moiety or a phenylethynyl group on the distinct meso position were synthesized under statistical conditions according to Lindsey's method [START_REF] Lindsey | Synthesis of tetraphenylporphyrin under very mild conditions[END_REF]. The pentabrominated key precursor and its porphyrinic boronic acid pinacol ester coupling partner were submitted to Suzuki-Miyaura reaction conditions in the presence of Pd(dppf)Cl2 as catalyst and cesium carbonate as base at 100 °C in a DMF/water system (99:1). The desired gear carrying five porphyrin paddles and 4,4'-biphenyl spacers was obtained in 34% yield. Extension of the cogwheel diameter was next attempted by reacting the pentaiodinated precursor with the alkynylporphyrin under milder conditions involving Pd(PPh3)2Cl2 and CuI as catalysts in triethylamine at 45 °C. The pentaporphyrin gear resulting from a five-fold Sonogashira reaction and exhibiting a diameter over 5 nm was obtained in 62% yield.

All these gear prototypes were fully characterized by standard techniques involving mass spectrometry and NMR spectroscopy. The latter unambiguously showed that free rotation of the upper platform is maintained at room temperature, even in the most sterically hindered architectures.

In view of on-surface studies, it was anticipated that a dissymmetry element in the cogwheels, acting as a tag, would be desirable to monitor by STM possible gearing effect. The design and synthesis of ruthenium complexes carrying a dissymmetrized cogwheel was thus tackled.

Dissymmetrized Cogwheels

How Can we Probe the Rotation using STM?

In the absence of time-resolution in STM imaging, molecular motion is probed by comparing images taken before and after the rotation event. When deposited on surface, the gear prototypes synthesized above will appear as pseudo C5-symmetric objects, in line with the cogwheel structures. Tracking and quantifying motion might thus be challenging. The presence of a tag, i.e. a chemical or steric variation lowering the object symmetry, appears highly desirable for in-depth mechanical studies at the molecular scale. As depicted on Figure 9, dissymmetrized cogwheels incorporating one distinct arm (in red) would allow for a straightforward differentiation between the initial configuration and the final state, resulting from disrotatory motion of neighboring molecules. It was thus envisioned to synthesize a family of star-shaped ruthenium complexes incorporating one tagged porphyrinic paddle. To this aim, the possibility to tune the length of the spacer between cyclopentadienyl and porphyrinic cores was exploited to incorporate one longer arm in the cogwheel structure. A single Sonogashira coupling on one halogenophenyl position of the ruthenium(II) key precursor would generate the longer phenylethynylphenyl spacer and subsequent four-fold Suzuki-Miyaura cross-couplings on the remaining positions would lead to the four shorter 4,4'-biphenyl linkers.

In view of the functionalization of one single arm via Sonogashira coupling, it is important to note that the five halogenated positions in the key building block are equivalent and thus react independently when submitted to statistical reactions conditions, leading to mixture of mono-and polysubstituted products. To overcome this issue, a chemoselective single Sonogashira reaction relying on the higher reactivity of aryl iodides compared to aryl bromides was targeted, and the corresponding penta(p-halogenophenyl)cyclopentadienyl ruthenium(II) precursor carrying one iodine and four bromine atoms was prepared [START_REF] Gisbert | Modular synthesis of pentaarylcyclopentadienyl Ru-based molecular machines via sequential Pd-catalysed cross couplings[END_REF].

Synthesis of a Dissymmetric Ruthenium Precursor

The dissymmetric ruthenium key precursor bearing one pre-activated position in view of a chemoselective single cross-coupling was obtained in four steps from tetra(p-bromophenyl)cyclopentadienone (Scheme 2). Introduction of the iodinated arm was performed by 1,2-addition of 4-iodophenyllithium to give the corresponding cyclopentadienol in 94% yield. Bromination using a mixture of hydrobromic and acetic acids almost quantitatively afforded bromocyclopentadiene as a mixture of three regioisomers. Subsequent reaction with ruthenium(0) cluster Ru3(CO)12 led to a selective insertion into the central C-Br bond to yield a single ruthenium(II) complex carrying the dissymmetrized penta(p-halogenophenyl)cyclopentadienyl ligand. Finally, ligand exchange in the presence of the thallium salt of thioether-functionalized tripod afforded the desired dissymmetric precursor in 38% overall yield. This dissymmetric penta(p-halogenophenyl)cyclopentadienyl ruthenium(II) key building block was then used for the selective synthesis of a gear prototype with a sterically-tagged cogwheel.

Synthesis of a Dissymmetric Pentaporphyrinic Cogwheel

As shown on Scheme 3, the dissymmetrized key precursor was engaged in sequential cross-coupling reactions, to selectively install the longer tooth in a first step and subsequently insert the four remaining shorter teeth. It is important to note that the nickel porphyrin structure remains identical in the five paddles and dissymmetry only arises from the length of the linkers.

The Sonogashira coupling was carried out under mild conditions in the presence of the A3B-type porphyrin A bearing a terminal alkyne to chemoselectively functionalize the iodinated position of the precursor. Using PdCl2(PPh3)2 and CuI as catalysts in a mixture of tetrahydrofuran and triethylamine (4:1), the desired monoporphyrinic ruthenium complex was isolated in 51% yield after 24h at 45 °C. This monofunctionalized intermediate was next reacted with a large excess of A3B-type porphyrin B bearing a boronic ester in the presence of cesium carbonate as base and PdCl2(dppf) as catalyst. After 48h at 100 °C in a DMF/water (99:1) mixture, all the remaining p-bromophenylene groups were functionalized and the gear prototype carrying five identical porphyrin fragments but different spacers was obtained in 36% yield [START_REF] Gisbert | Modular synthesis of pentaarylcyclopentadienyl Ru-based molecular machines via sequential Pd-catalysed cross couplings[END_REF].

Conclusion and Perspectives

Alternative strategies are now developed to obtain dissymmetric gears with spacers of identical length, using various porphyrin structures. For that purpose, chemoselective conditions of Suzuki-Miyaura couplings must be identified to discriminate iodoaryl versus bromoaryl groups. Work is also underway to study such dissymmetric molecular gears on surface.

Figure 1 .

 1 Figure 1. Side view of a planthopper Issus coleoptratus nymph (left) and Scanning Electron Microscopy image of meshed micrometric gears located on the hind legs (right). From Ref. 35. Adapted with permission from AAAS.

Figure 2 .

 2 Figure 2. Molecular gears proposed by K. Mislow [38] (left), H. Iwamura [37] (center) and J. Siegel [39] (right), all are based on triptycene cogwheels.

Figure 3 .

 3 Figure 3. Chemical structure (left) and schematic representation (right) of the engaged and disengaged molecular gears proposed by Shionoya et al. (adapted from Ref. 40).

Figure 4 .

 4 Figure 4. STM images (A) showing the displacement of a pinion (single molecule) along a rack (self-assembled monolayer of the same molecule) on Cu(111). The white arrow gives the orientation of the molecule according to the pyrimidine tagged tooth. A macroscopic rack and pinion (B) and the chemical structure of the molecule (C). From Ref. 41, adapted with permission from Springer Nature.

Figure 5 .

 5 Figure 5. Expected transmission of rotation from one molecule to its neighbor using a STM tip as of mechanical energy.

Figure 6 .

 6 Figure 6. Structure of the parent compound, a molecular motor [29] (left), and of the cogwheels with five mono-dimensional arms (center) and with five bi-dimensional paddles (right).

Figure 7 .

 7 Figure 7. Chemical structure of the three gear prototypes with mono-dimensional arms and respective yields of the quintuple cross-coupling reaction to form them.

Figure 8 .

 8 Figure 8. Chemical structure of the four gears with bi-dimensional paddles and respective yields of the quintuple cross-coupling reaction to form them.

Figure 9 .

 9 Figure 9. Principle of the motion transmission through a molecular gear train actuated by a STM tip. Initial configuration (left) and final configuration (right) after a fifth of a turn (72°). The first gear rotates clockwise pushed by the STM tip and induces the counterclockwise rotation of the next molecule.

Scheme 2 .

 2 Scheme 2. Synthesis of 1-(p-iodophenyl)-2,3,4,5-tetra(p-bromophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II).

Scheme 3 .

 3 Scheme 3. Synthetic route to the dissymmetrized gear prototype. One of the spacers between the cyclopentadienyl ligand and the porphyrins contains an additional ethynyl fragment. Ar = 3,5 di-tert-butylphenyl.This first example of a dissymmetric ruthenium-based molecular gear was thus obtained in two steps from 1-(p-iodophenyl)-2,3,4,5-tetra(p-bromophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II) via sequential chemoselective Sonogashira / four-fold Suzuki-Miyaura cross-couplings.

Acknowledgements

This work was supported by the University Paul Sabatier (Toulouse, France) and the CNRS. It has received funding from the Agence Nationale de la Recherche (ANR) (ACTION project ANR-15-CE29-0005) and from the European Union's Horizon 2020 research and innovation program under the project MEMO, grant agreement No 766864. This research was also partly supported by the JSPS KAKENHI grant in aid for Scientific Research on Innovative Areas "Molecular Engine (No.8006)" 18H05419. Dr. Colin Martin is warmly acknowledged for his careful reading and improving of our manuscript.


Yohan Gisbert

Agnès M Sirven

Gwénaël Rapenne

Claire Kammerer

Design and Synthesis of a Nano-winch

Keywords:

Technical progress in the field of Scanning Probe Microscopy (SPM) has opened the way for the development of new surface-mounted artificial molecular machines, which can be addressed at the single molecular scale. In this context, a ruthenium-based molecular motor has been shown to undergo controlled unidirectional and reversible rotation when fueled with electrons delivered by the tip of a Scanning Tunneling Microscope. In this chapter, we report our efforts towards a deeper understanding of the mechanical properties of this molecular motor. In view of complementary force measurements to be performed at the single molecule scale using SPM techniques, the organometallic structure of the motor has been derivatized to append a long chain terminated by a hook. We detail here the design of this nano-winch architecture and the modular synthesis of a first prototype dedicated to Atomic Force Microscopy-based Single Molecule Force Spectroscopy experiments.

Introduction

In the field of molecular machines, [START_REF] Balzani | Molecular Devices and Machines. Concepts and Perspectives for the Nanoworld[END_REF] molecular motors represent a subclass of systems able to convert various sources of energy into unidirectional mechanical motion. In Nature, biological molecular motors are ubiquitous and commonly exploit chemical energy recovered from ATP hydrolysis or electrochemical potential gradients as energy input. [START_REF] Saper | Synthetic systems powered by biological molecular motors[END_REF] Well-known examples of biomolecular motors inducing linear motion include myosins and kinesins, responsible in particular for muscle contraction and intracellular cargo transport. In contrast, rotary motion is generated in bacterial flagellar motors and in ATP synthases, for which reversibility of the rotation allows mutual conversion of chemical energy and electrochemical potential. These motors thus accomplish a variety of complex chemical and mechanical tasks, vital to biological systems. The operating conditions at the nanoscale involve high viscosity and constant Brownian motion, which has to be harnessed in order to ensure directionality in the movements. Strategies to reduce degrees of freedom and allow out-of-equilibrium operating conditions have been implemented by evolution, such as tracks for linear motors or compartmentalization by lipid barriers for rotary motors. This organization is critical for the collective emergence of useful work.

Far from the complexity of biological systems, chemists have designed and synthesized artificial molecular machines over the past forty years, with the aim of triggering controlled large-amplitude motions in response to a broad range of stimuli (light, electrochemistry, pH, bond formation/cleavage, ion binding, etc…). [START_REF] Kay | Synthetic molecular motors and mechanical machines[END_REF][START_REF] Erbas-Cakmak | Artificial molecular machines[END_REF][START_REF] Baroncini | Making and operating molecular machines: a multidisciplinary challenge[END_REF] The tremendous efforts in this new field were recognised by the 2016 Nobel Prize in Chemistry, awarded to Jean-Pierre Sauvage, [START_REF] Sauvage | From chemical topology to molecular machines (Nobel Lecture)[END_REF] Sir Fraser Stoddart [START_REF] Stoddart | Mechanically interlocked molecules (MIMs)-molecular shuttles, switches, and machines (Nobel Lecture)[END_REF] and Ben Feringa [START_REF] Feringa | The art of building small: from molecular switches to motors (Nobel Lecture)[END_REF] for their major contributions. In particular, control of directionality in translational and rotational systems was tackled in order to ultimately obtain molecular motors, able to perform work by progressive and repetitive operations. Since the late 1990s, many types of chemicallyfueled and light-fueled motors have been reported, based on diverse architectures and mechanisms. [START_REF] Kassem | Artificial molecular motors[END_REF][START_REF] García-López | Light-activated organic molecular motors and their applications[END_REF][START_REF] Baroncini | Photo-and redox-driven artificial molecular motors[END_REF][START_REF] Goswami | Nano)mechanical motion triggered by metal coordination: from functional devices to networked multicomponent catalytic machinery[END_REF] Seminal work by Kelly et al. on a ratchet-type compound based on triptycene and helicene units led to an important milestone, with a 120° unidirectional rotation around a C-C single bond driven by successive chemical steps. [START_REF] Kelly | Unidirectional rotary motion in a molecular system[END_REF] Light driven directional rotary motion was initially developed by Feringa et al. in chiral overcrowded alkenes, in which successive photoisomerization and thermal relaxation steps induced repetitive unidirectional 360° rotation around C=C double bonds. [START_REF] Koumura | Light-driven monodirectional molecular rotor[END_REF] Chemically-and light-fueled translational motors were also conceived, as exemplified by the molecular walkers [START_REF] Von Delius | A synthetic small molecule that can walk down a track[END_REF] reported by Leigh et al., and by various mechanically-interlocked molecules such as catenanes [START_REF] Leigh | Unidirectional rotation in a mechanically interlocked molecular rotor[END_REF] and rotaxanes. [START_REF] Chatterjee | Beyond switches: ratcheting a particle Energetically uphill with a compartmentalized molecular machine[END_REF][START_REF] Serreli | A molecular information ratchet[END_REF] These systems have been mostly studied in solution, which hampers the recovery of work due to random orientation of the population of molecular motors. Collective behaviours were however obtained after suitable organization of the assemblies of motors, leading to the emergence of controlled motion up to the macroscale. [START_REF] Dattler | Design of collective motions from synthetic molecular switches, rotors, and motors[END_REF] In this regard, the light-fueled overcrowded alkenes developed by Feringa et al. have been intensively studied, among others, and led upon irradiation to the rotation of a micrometric glass rod deposited over a liquid crystal phase doped with the motor, [START_REF] Eelkema | Nanomotor rotates microscale objects[END_REF] or to the macroscopic contraction of a polymeric gel incorporating the motor as reticulation unit. [START_REF] Li | Macroscopic contraction of a gel induced by the integrated motion of light-driven molecular motors[END_REF] Organization on surface also promoted collective behaviours of rotaxane-based machines, leading to reversible bending of cantilever beams in response to chemical stimuli, [START_REF] Huang | A nanomechanical device based on linear molecular motors[END_REF] or to directional transport of a droplet under irradiation. [START_REF] Berná | Macroscopic transport by synthetic molecular machines[END_REF] The latter examples highlight the frequent adaptation to interfacial conditions of systems initially designed to be operated in solution.

Alternatively, several research groups adopted the opposite strategy and considered adsorption on surface as key requirement for the molecular design, in view of controlling the relative orientation of the motors. On-surface studies were also considerably facilitated by the technical progress made in the field of Scanning Probe Microscopy. In particular, thanks to the high-resolution imaging capabilities of Scanning Tunneling Microscopy (STM), it has been possible to precisely study motions on surface of entire molecules and within molecules, at the single molecular scale and in self-assemblies. STM is not only a tool to probe organization and motion on surface, but it can also be used for the mechanical manipulation of atoms and molecules, which is crucial to gain knowledge in fundamental processes occurring at the nanoscale. [START_REF] Grill | Rolling a single molecular wheel at the atomic scale[END_REF][START_REF] Manzano | Step-by-step rotation of a molecule-gear mounted on an atomic-scale axis[END_REF] Moreover, the tip of the STM can act as a localized atomic scale electrode, particularly appealing for the development of electron-fueled molecular motors. Since the report of a surface-bound butyl methyl sulfide by Sykes in 2011, [START_REF] Tierney | Experimental demonstration of a single-molecule electric motor[END_REF] several electrically-driven systems have been developed, undergoing on metallic surfaces controlled unidirectional translational [START_REF] Kudernac | Electrically driven directional motion of a four-wheeled molecule on a metal surface[END_REF] or rotational motion. In the latter case, rotation of the whole molecule around an anchoring point can occur (the surface acts as stator) [START_REF] Tierney | Experimental demonstration of a single-molecule electric motor[END_REF][START_REF] Eisenhut | Inducing the controlled rotation of single o-MeO-DMBI molecules anchored on Au(111)[END_REF][START_REF] Simpson | How to control single-molecule rotation[END_REF] or motion can be restricted to one sub-molecular fragment rotating around an internal degree of freedom (the stator subunit is then anchored onto the surface). [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF][START_REF] Zhang | A chiral molecular propeller designed for unidirectional rotations on a surface[END_REF] It is important to note here that such molecular motors have been studied at low temperature, thereby decreasing random thermal fluctuations and increasing control over targeted electrically-driven motion. In these conditions, our group demonstrated the reversible unidirectional rotation of a piano-stool ruthenium complex studied at the single molecule scale. [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF] From macro-to nano-scale motors, central questions concern their efficiency and the useful work they are able to perform. [START_REF] Browne | Making molecular machines work[END_REF] On these aspects, biological systems outcompete artificial molecular motors, as their evolution was driven by functionality, and as they achieve energy conversion efficiencies over 40%, along with a force-permass ratio comparable to that of modern macroscale engines. [START_REF] Marden | Scaling of maximum net force output by motors used for locomotion[END_REF][START_REF] Hess | Engineering with biomolecular motors[END_REF] To get further insight on the intrinsic performances of our surface-bound electron-fueled ruthenium-based molecular motor, incorporation of the organometallic scaffold into a winch structure was envisioned, allowing for various force measurements at the single molecule scale.

A Reversible Electron-Fueled Molecular Motor

Since the early 2000s, our group has designed and synthesized a series of electrically-driven azimuthal rotors, [START_REF] Vives | Prototypes of molecular motors based on star-shaped organometallic ruthenium complexes[END_REF][START_REF] Stefak | Desymmetrization on both ligands of pentaphenylcyclopentadienylhydrotris(indazolyl)borate ruthenium(II) complexes: Prototypes of organometallic molecular gears and motors[END_REF][START_REF] Kammerer | Biomimetic and technomimetic single molecular machines[END_REF] to be studied on surface as single molecules [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF][START_REF] Zhang | A chiral molecular propeller designed for unidirectional rotations on a surface[END_REF] or as self-assemblies [START_REF] Zhang | Simultaneous and coordinated rotational switching of all molecular rotors in a network[END_REF] by means of STM. Electric energy delivered by the STM tip is converted into a rotation movement, which was shown to be unidirectional and reversible in the case of a piano-stool ruthenium complex incorporating a dissymmetric rotor subunit (Figure 1). [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF]

Architecture of the Organometallic Motor

The architecture of the unidirectional and reversible electron-fueled molecular motor is based on a piano-stool ruthenium(II) complex, involving a hydrotris(indazolyl)borate ligand as tripodal stator and a pentaarylcyclopentadienyl platform as rotor. The central ruthenium atom thus acts as a linker between both subunits, but also as ball bearing to favour azimuthal rotation over other degrees of freedom (Figure 1). The rigid hydrotris(indazolyl)borate scaffold exhibits a dual function: the facial coordination of the nitrogens to the ruthenium center lifts the upper rotor subunit away from the surface, while an appropriate functionalization on the opposite face allows tight anchoring on surface. [START_REF] Kammerer | Scorpionate hydrotris(indazolyl)borate ligands as tripodal platform for surface-mounted molecular motors and gears[END_REF] Indeed, the three ethylthioether groups appended to the indazole moieties provide high stability on metallic surfaces by preventing translation, rotation and rocking motions of the stator. The rotating subunit is a rigid aromatic platform based on a central cyclopentadienyl moiety carrying four identical ferrocenylphenyl arms and one shorter tolyl arm. This structural dissymmetry finds two origins. First, in the absence of time-resolution in STM, molecular motion is probed by comparing static images and following a chemically or sterically "tagged" part of the molecule. Here, the shorter tolyl arm acts as a tag, which is easily traceable on STM images. Second, with the aim of achieving unidirectional rotation, the symmetry of the rotor had to be lowered as compared to the parent pseudo C5 penta(ferrocenylphenyl)cyclopentadienyl ligand, so as to generate a dissymmetric energy landscape for rotary motion.

Synthesis and On-Surface Characterization

Molecular motor 6 was obtained in five steps starting from cyclopenta-2,4-dienone 1, incorporating four identical p-bromophenylene arms in view of further functionalization with ferrocene moieties in the final step (Scheme 1). [START_REF] Vives | Directed synthesis of symmetric and dissymmetric molecular motors built around a ruthenium cyclopentadienyl tris(indazolyl)borate complex[END_REF] Introduction of the fifth arm was achieved via 1,2-addition of p-tolylmagnesium bromide to yield the corresponding cyclopentadienol, which was subsequently converted into bromocyclopentadiene 2 under acidic conditions. Bromocyclopentadiene 2 was obtained in 55% yield over two steps, as a 2:2:1 mixture of regioisomers. Oxidative addition on ruthenium(0) cluster Ru3(CO)12 afforded half-sandwich ruthenium complex 3, which underwent ligand exchange in the presence of the thioether-functionalized potassium hydrotris(indazolyl)borate 4.K to yield the precursor of the dissymmetrized motor 5. Finally, a four-fold Pd-catalyzed Suzuki-Miyaura coupling with ferroceneboronic acid led to molecular motor 6 in 52% yield. After full characterization, the solid ruthenium complex 6 was deposited by sublimation on a Au(111) surface and subsequently studied by STM under ultra-high vacuum (UHV) at low temperature at the single molecule scale. STM images confirmed that some complexes remain intact after deposition and are adsorbed on the surface via the three thioether anchoring groups, as expected. At 80 K, the molecule undergoes rotation of the upper cyclopentadienyl ligand around the B-Ru axis, thereby confirming that this is the privileged degree of freedom. However, this rotation is purely related to Brownian motion and is thus a random oscillation with no directionality. Interestingly, when the temperature is lowered to 5 K, the motion is stopped and a contrast between the two different types of arms is observed on STM images, as expected from the incorporation of a tag on the rotor subunit. [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF] Scheme 1. Synthesis of the ruthenium-based molecular motor in five steps, starting from 2,3,4,5-tetra(p-bromophenyl)cyclopenta-2,4-dienone.

Electron-Fueled Unidirectional and Reversible Rotation

At 5 K, excitation of the motionless complex by a voltage pulse delivered on one arm by the STM tip induces a unidirectional rotation of the upper rotor subunit. In this set-up, motion is thus triggered by an inelastic electron tunnelling process leading to stepwise rotation with angles being multiples of 24°, in line with the predicted 15 potential wells in a full 360° rotation. [START_REF] Perera | Controlled clockwise and anticlockwise rotational switching of a molecular motor[END_REF] Directionality originates from the asymmetric character of the energy landscape in the excited state, itself related to the dissymmetric architecture of the complex. Moreover, it was observed that the direction of rotation directly depends on the nature of the excited arm, i.e. on the nature of the excited state that is addressed. The direction can thus be reversed at will by locating the STM tip apex above one of the ferrocenyl arms or above the truncated arm (Figure 2). This organometallic structure, deposited on surface and studied as a single molecule at low temperature under ultra-high vacuum, was thus shown to convert electric energy provided by the STM tip into reversible directed motion. Following this breakthrough, new questions arose about the forces developed by this rotary motor and its ability to provide useful work, and thorough mechanical studies were thus envisioned.

Towards Complementary Mechanical Studies of the Molecular Motor: the Nanowinch

To gain insight in the mechanical properties of the ruthenium-based rotary motor, complementary direct and indirect studies were devised. Both approaches allow to probe forces exerted by single molecules, but they rely on different operating conditions and scanning probe microscopy techniques. In a direct approach, force spectroscopy experiments will be performed by means of an atomic force microscope (AFM) at the solid-liquid interface in ambient conditions to determine the stall force of the rotary motor. In a second approach, the surface-bound motor will be loaded with various molecular fragments adsorbed on surface, and the electrically-driven mechanical motion of the motor at low temperature in UHV will be studied by STM as a function of the loading. In both cases, it appears necessary to derivatize the motor structure and append a long chain, crucial for Single Molecule Force Spectroscopy (SMFS) experiments and for the connection of molecular loads. Following technomimetic principles of molecular machine design, [START_REF] Rapenne | Synthesis of technomimetic molecules: towards rotation control in single-molecular machines and motors[END_REF][START_REF] Gakh | Molecular Devices. An introduction to Technomimetics and Biological Applications[END_REF] this derivatized rotary motor displaying a long chain can be viewed as a nano-winch. &"#'$/ '"%07/ #'+$'/ %'$7&', 2#5"0&8' L %' "' 3 &$"44+0' , 2#5"0&<' 0/ ="4&%$' "%07/ #+%; ' +, ' +%. &&. ' $7&' / %41' : "1' $/ ' "=/ +. ' . +552, +/ %' +%' / #. &#' $/ ' 0/ %$#/ 4'$7&'"#07+$&0$2#&'/ 5'"'$#"+%'/ 5'; &"#, '>$7&+#', $"-4&'*/ , +$+/ %+%; '"4/ %; '"'4+%&'"%. '$7&'. +, $"%0&' -&$: &&%'$: / ', 200&, , +=&'; &"#, B8'@ / '/ 2#'K%/ : 4&. ; &<'$#"%, 3 +, , +/ %'/ 5'3 / $+/ %'5#/ 3 '"', +%; 4&'3 / 4&024&' $/ ' $7&' %&) $' 7", ' %&=&#' -&&%' / -, &#=&. 8' F 4$7/ 2; 7' $7+, ' *#/ M &0$' +, ' $#241' 52%. "3 &%$"4<' +$' : / 24. ' -&' +3 */ #$"%$' $/ ' 3 ", $&#' , 207' $#"%, 3 +, , +/ %' / 5' 3 / $+/ %' "$' $7&' %"%/ , 0"4&' 5/ #' &%&#; 1' 7"#=&, $+%; ' "%. ' *#/ . 20$+/ %<'. "$"'+%*2$'/ %'"%'"$/ 3 +0', 0"4&'0+#02+$'/ #'5/ #'+%5/ #3 "$+/ %'&%0/ . +%; 8''' ' F '2%+H2&'", *&0$'/ 5'/ 2#'. &, +; %'+, '$7&'*/ , , +-+4+$1'$/ '0/ ="4&%$41'"$$"07'$7&'; &"#, '/ %'$7&', 2#5"0&8' @ 7&' $: / ' *2-4+, 7&.

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Proj e t ACTI ON D OCU M EN T SCI EN TI FI

Design of a Nano-winch Architecture

As in a macroscopic winch, the nanometer-sized counterpart will include three main parts: the motor, a long rope and a terminal hook to attach loads. The structure of the ruthenium-based rotary motor will thus be integrated in the nano-winch, in a way to maintain directionality and reversibility in the electron-fueled motion. This implies to operate minimal changes both in the architecture of the complex and in its electronic structure. It was thus envisioned to connect the long chain to the truncated arm of the cyclopentadienyl rotor, and use a chemical spacer to minimize steric and electronic interactions (Figure 3). Polyethylene glycol (PEG) was selected as polymeric chain, since it exhibits the required adsorption properties for AFM-based force spectroscopy experiments. Additionally, the availability of monodisperse PEG chains with a broad range of polymerisation degrees is an asset to fine tune mechanical studies, and adjust the length of the chain depending on the operating conditions in the direct and indirect approaches. Finally, a chemical hook located at the PEG chain extremity will allow the connection of various molecular loads.

Direct Strategy: AFM-Based Single Molecule Force Spectroscopy on an Unloaded Nano-winch

AFM-based single molecule force spectroscopy allows to probe mechanical forces in individual molecules and has been used to investigate various biological and artificial systems, [START_REF] Willet | Molecular Manipulation with Atomic Force Microscopy[END_REF] including small molecular machines such as rotaxanes [START_REF] Lussis | A single synthetic small molecule that generates force against a load[END_REF] and catenanes. [START_REF] Quaethem | Probing the mobility of catenane rings in single molecules[END_REF] AFM-based force spectroscopy is performed at the solid-liquid interface on surface-bound single molecules, i.e. the nano-winch will be adsorbed on a gold surface in a dilute distribution and immersed in a high boiling-point solvent. Bringing the AFM tip into contact with the surface will allow the PEG chain of a single nano-winch to adsorb on the tip, and the latter will be progressively moved away from the surface, leading to a stretching of the PEG chain (Figure 4). It is important to note that these experiments will be carried out at room temperature, meaning that the ruthenium-based motor will undergo random thermal motion and particularly random oscillation of the cyclopentadienyl platform. This rotation will be stopped by moving the tip further away from the surface, and the force applied on the nano-winch at that stage will give access to the stall force of the motor. From a structural point of view, the nano-winch used in such force spectroscopy experiments will require a long PEG chain of ca. 8 nm, with a non-functionalized end. As starting point, a methoxy-terminated PEG-24 chain could thus be connected to the motor, and further fine tuning of the tether length will be possible provided a modular synthetic route towards nano-winches is devised.

Indirect Strategy: STM Study of a Loaded Nano-winch

In this alternative strategy, our aim is to study by UHV-STM at low temperature the electrically-driven rotary motion of the loaded motor, i.e. of the nano-winch connected to various molecular fragments (Figure 5). [START_REF] Ohmann | Supramolecular rotor and translator at work: on-surface movement of single atoms[END_REF] After deposition on Au(111) and subsequent adsorption of the motor subunit linked to its load, lateral mechanical manipulation of the load will be performed with the STM tip at 77 K to extend the PEG chain. This layout will then be frozen by lowering the temperature to 5 K and the rotation of the motor will be triggered by a voltage pulse on one of the motor arms. Directional rotation of the rotor subunit is expected to result in a translation of the load if the force output of the motor is sufficient. It is important to note that gravity is irrelevant at the nanoscale, and the term "load" is thus not related here to weight but refers to the force exerted by the molecular fragment on the motor. Using fragments with increasing diffusion energies upon adsorption on surface, the maximal output force of the motor will be surpassed at some point, as witnessed by the absence of translation of the load. Comparison of the diffusion energies of the last translated fragment and of the first motionless one will thus give an estimation of the maximal work delivered by the single-molecule motor, and by extension of its maximal output force. From a structural point of view, the length of the PEG chain should be much shorter than for force spectroscopy experiments, and a PEG-8 building block is envisioned as starting point. The loads should be covalently bound to the chain under reliable, mild and high-yielding conditions, which is reminiscent of click reaction requirements. [START_REF] Kolb | Click chemistry: diverse chemical function from a few good reactions[END_REF] An azide function will thus act as a hook to allow for azide-alkyne cycloaddition, yielding a 1,2,3triazole as connector between the chain and the load. Three different molecular loads displaying a terminal alkyne function have been synthesized, with incremental numbers of triptycenyl units to induce increasing diffusion energies on surface (Figure 6). [START_REF] Sirven | Synthesis of functionalized mono-, bis-, and trisethynyltriptycenes for one-dimensional self-assembly on surfaces[END_REF] Figure 6. Structures of the three molecular loads already available, displaying a terminal alkyne function and incremental numbers of triptycenyl units. The yields over the complete synthetic sequence are given below.

4 Synthesis of the Nano-winch

Preliminary Synthetic Studies and Selection of an Appropriate Spacer

In preliminary synthetic studies, attempts were made to graft the PEG chain of the nano-winch directly on the truncated arm of the motor by replacing the tolyl moiety with a PEGylated phenyl ether group.

[49] However, this approach failed to afford the desired compound and introduction of a spacer between the rotor phenylene unit and the PEG chain was envisioned. This spacer should exhibit two functions: it should allow spacial and electronic decoupling of the motor from the chain, and favour modular syntheses of nano-winches via late-stage functionalization of the motor scaffold with variable PEG derivatives. Following these guidelines, the N-propargyl amide fragment appeared particularly attractive due to the high availability of monodisperse carboxylic acid-terminated PEG-chains.

In our modular synthetic strategy, the common key precursor thus incorporates a dissymmetrized cyclopentadienyl ligand, with four phenylferrocenyl arms and a single phenylpropargyl amine arm. Final stage condensation with the appropriate PEGylated carboxylic acid derivative delivers the targeted nano-winch structure. However, due to the limited stability of the free propargyl amine derivative, it was decided to use the tert-butyloxycarbonyl-protected (BOC-protected) parent compound 7 as common precursor (Figure 7).

Modular Synthetic Strategy towards a Common Nano-winch Precursor

With the N-propargyl amide fragment selected as spacer for the diverse nano-winch prototypes, the synthetic route to the BOC-protected propargyl amine common precursor 7 was devised.

As for the parent molecular motor, the presence of a dissymmetrized rotating subunit requires the discrimination of one arm along the synthesis. Introduction of the distinct phenylpropargyl amine moiety may be performed at an early stage via a nucleophilic addition on 2,3,4,5-tetra(p-bromophenyl)cyclopenta-2,4-dienone 1, similarly to the molecular motor synthetic route described above (Scheme 1). However, this linear strategy inherently limits the structural diversity of the winch spacers, and issues for the coordination to ruthenium may also be encountered with a pre-functionalized cyclopentadiene derivative. A modular strategy was thus devised, involving a late-stage functionalisation of a 1,2,3,4,5-penta(p-halogenophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II) precursor, carrying one single activated p-iodophenyl group and four p-bromophenyl moieties. [START_REF] Gisbert | Modular synthesis of pentaarylcyclopentadienyl Ru-based molecular machines via sequential Pd-catalysed cross couplings[END_REF] This strategy exploits the enhanced reactivity of aryl iodides compared to aryl bromides in palladium-catalyzed crosscouplings, and more particularly under Sonogashira conditions. The dissymmetrized precursor 11, with a single p-iodophenyl arm, would then allow for a chemoselective Sonogashira cross-coupling to install the N-protected propargyl amine function, followed by a four-fold cross-coupling to incorporate the ferrocenyl moieties on the remaining brominated positions. More generally, this modular strategy was also applied to the synthesis of dissymmetric molecular gear prototypes via sequential cross-couplings (see chapter 5 "Prototypes of molecular gears with an organometallic piano-stool architecture" in this book).

The synthesis of the dissymmetrized 1-(p-iodophenyl)-2,3,4,5-tetra(p-bromophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II) complex 11 was carried out in four steps starting from 2,3,4,5-tetra(p-bromophenyl)cyclopenta-2,4-dienone 1 (Scheme 2). Introduction of the iodinated arm was performed by 1,2-addition of 4-iodophenyllithium to give the corresponding alcohol 8, which was smoothly converted to 5-bromocyclopenta-1,3-diene 9, obtained as a mixture of three regioisomers. Subsequent reaction with ruthenium(0) cluster Ru3(CO)12 led to a selective insertion into the central C-Br bond to yield ruthenium(II) complex 10, carrying a dissymmetrised penta(p-halogenophenyl)cyclopentadienyl ligand. Finally, ligand exchange in the presence of the thallium salt of thioether-functionalized hydrotris(indazolyl)borate 4.Tl afforded the desired precursor 11 in 38% overall yield. The key pentahalogenated building block, carrying one pre-activated p-iodophenyl arm, was next engaged in sequential chemoselective cross-couplings to introduce successively the N-protected propargyl amine moiety followed by the four ferrocenyl groups (Scheme 3). The Sonogashira reaction was carried out under mild conditions using tert-butyloxycarbonyl-protected propargyl amine as coupling partner in the presence of Pd(0) and Cu(I) cocatalysts in a THF/triethylamine mixture at 40 °C. Chemoselective functionalization of the p-iodophenyl group was achieved to afford ruthenium complex 12 in 75% yield. In the next step, the four remaining p-bromophenyl moieties were engaged in Suzuki-Miyaura cross-couplings with ferrocene boronic acid pinacol ester as a coupling partner, in the presence of PdCl2(dppf) as a catalyst and a large excess of cesium carbonate as a base in a DMF/water system. The desired tetraferrocenyl product 7 was obtained in 16% yield, which corresponds to a yield of 63% per C-C bond newly formed. Scheme 3. Two-step synthesis of nano-winch key precursor 7 via chemoselective sequential cross-coupling reactions.

The ruthenium complex 7, carrying four phenylferrocenyl arms and a single BOC-protected phenylpropargyl amine arm, was obtained in six steps from 2,3,4,5-tetra(p-bromophenyl)cyclopenta-2,4-dienone 1 in 4.6% overall yield. This compound was used as key building block in the synthesis of various nano-winch prototypes, since it proved stable enough to be stored for several months, as opposed to the corresponding deprotected amine. The preparation of each nano-winch prototype, dedicated to targeted mechanical studies, was thus further achieved in two steps involving propargyl amine deprotection followed by a condensation with the appropriate PEG chain.

Application to the Synthesis of an Unloaded Nano-winch for Single Molecule Force Spectroscopy Experiments

In view of Single Molecule Force Spectroscopy experiments, the first prototype of unloaded nano-winch was subsequently synthesized in two steps from the BOC-protected propargyl amine intermediate 7 (Scheme 4). For this first prototype, a long polyethylene glycol (PEG-24) chain was selected to ensure an efficient adsorption of the chain on the AFM tip. Deprotection of the propargyl amine moiety in 7 was conducted under mild conditions, using trimethylsilyl triflate in the presence of lutidine to give the corresponding free amine in 81% yield. Such unusual conditions for BOC cleavage were required to maintain a buffered medium, as the ruthenium(II) complex appeared unstable under standard acidic deprotection conditions. The free propargyl amine 13 then underwent condensation with the carboxylic acid-functionalized PEG chain to generate the desired N-propargyl amide spacer and thereby covalently link the long chain to the motor scaffold. To maximize the efficiency of this final synthetic step, monodisperse methoxy-PEG24-propionic acid activated as an N-hydroxysuccinimidyl ester was selected as coupling partner. Under very mild conditions involving triethylamine in DMF at room temperature, the target compound 14 was obtained in 85% yield. Full characterization unambiguously confirmed the connection of both the N-propargyl amide spacer and the PEG-24 chain to the molecular motor structure, leading to a first nano-winch prototype. AFM-based Single Molecule Force Spectroscopy studies on nano-winch 14 are currently underway.

Conclusion and Perspectives

A nano-winch architecture has been designed to get further insight in the mechanical properties of the electronfueled molecular motor developed in our group. In view of complementary force measurements at the single molecule scale, derivatization of the organometallic motor structure was performed by appending a long polyethylene glycol chain, possibly terminated by a hook. This general nano-winch architecture has to be adjusted according to the investigation technique, such as AFM-based Single Molecule Force Spectroscopy on the oscillating unloaded motor or as low-temperature STM studies on the loaded motor. The first nano-winch prototype incorporating a methoxy-terminated PEG24-chain has been successfully synthesized following a highly modular approach, and force spectroscopy measurements are currently underway to determine the stall force of the ruthenium-based motor. Synthetic efforts are now dedicated to the preparation of a new nano-winch prototype displaying a terminal chemical hook, such as an azide moiety, to covalently link molecular loads (Figure 8). Electron-fueled motion of the resulting loaded nano-winch will then indirectly give access to the maximal work delivered by this rotary motor.

Figure 1 .

 1 Figure 1. Structure of the ruthenium-based molecular motor adsorbed on a gold surface and related electron-fueled unidirectional rotation.

Figure 2 .

 2 Figure 2. Electrically-driven unidirectional and reversible rotation of the ruthenium-based molecular motor, on Au(111) surface at low temperature. The direction of rotation can be reversed at will by locating the STM tip apex above one of the ferrocenyl arms (right image, counterclockwise rotation) or above the truncated tolyl arm (left image, clockwise rotation).

QUE 8 ! 8 !

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Figure 3 .

 3 Figure 3. Architecture of the nano-winch, including the rotary motor subunit linked via a chemical spacer to a long PEG chain terminated by a hook.

Figure 4 .

 4 Figure 4. Principle of the AFM-based Single Molecule Force Spectroscopy experiments, performed at the solid-liquid interface under ambient conditions.

Figure 5 .

 5 Figure 5. Principle of the LT-UHV-STM experiments on the nano-winch connected to various molecular loads, adsorbed on a gold surface. Rotary motion of the motor is triggered by a voltage pulse and subsequent translational motion of the load occurs if the maximal output force of the motor is sufficient.

Figure 7 .

 7 Figure 7. Structure of the key precursor to various nano-winches, featuring a tert-butyloxycarbonyl-protected propargyl amine fragment.

Scheme 2 .

 2 Scheme 2. Synthesis of 1-(p-iodophenyl)-2,3,4,5-tetra(p-bromophenyl)cyclopentadienyl hydrotris(indazolyl)borate ruthenium(II) key intermediate.

Scheme 4 .

 4 Scheme 4. Synthesis of the first nano-winch prototype dedicated to Single Molecule Force Spectroscopy experiments, in two steps from BOC-protected propargyl amine derivative 7.

Figure 8 .

 8 Figure 8. Structure of a future nano-winch prototype carrying an azide hook, in view of subsequent loading with alkynylderived molecular fragments.

Acknowledgements

This work was supported by the University Paul Sabatier (Toulouse, France) and CNRS. It has received funding from the Agence Nationale de la Recherche (ACTION project ANR-15-CE29-0005) and from the European Union's Horizon 2020 research and innovation program under the project MEMO, grant agreement No 766864. This research was also partly supported by the JSPS KAKENHI grant in aid for Scientific Research on Innovative Areas "Molecular Engine (No.8006)" 18H05419. Y.G. thanks the MESR for a PhD Fellowship. A.M.S. thanks the Physics Institute of CNRS and the Région Midi-Pyrénées for a PhD Fellowship.