Molecular Rotary Motors: Unidirectional Motion Around

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SPECIAL FEATURE: PERSPECTIVE

Molecular rotary motors: Unidirectional motion

around double bonds SPECIAL FEATURE: PERSPECTIVE

Diederik Rokea, Sander J. Wezenberga,1, and Ben L. Feringaa,1

Edited by J. Fraser Stoddart, Northwestern University, Evanston, IL, and approved April 6, 2018 (received for review January 17, 2018)

The field of synthetic molecular machines has quickly evolved in recent years, growing from a fundamental curiosity to a highly active field of chemistry. Many different applications are being explored in areas such as catalysis, self-assembled and nanostructured materials, and molecular electronics. Rotary molecular motors hold great promise for achieving dynamic control of molecular functions as well as for powering nanoscale devices. However, for these motors to reach their full potential, many challenges still need to be addressed. In this paper we focus on the design principles of rotary motors featuring a double-bond axle and discuss the major challenges that are ahead of us. Although great progress has been made, further design improvements, for example in terms of efficiency, energy input, and environmental adaptability, will be crucial to fully exploit the opportunities that these rotary motors offer. molecular motor | alkene | molecular machine

Control of motion at the molecular scale has intrigued expansion of gels (29), and actuation of nanofibers in chemists for a very long time. The quest for overcoming response to their environment (35). This leap from random thermal (Brownian) motion has culminated in static to dynamic materials clearly demonstrates the the emergence of synthetic molecular machines (1–7), potential of molecular machines. Although much ef- including motors (8–12), muscles (13), shuttles (14), fort has already been devoted to the development of elevators (15), walkers (16), pumps (17–19), and assem- molecular motors and machines as well as the eluci- blers (20). By taking inspiration from the fascinating dation of their operational mode, a great deal of de- dynamic and motor functions observed in biological sign improvements are needed to fully exploit the systems (e.g., ATPase and bacterial flagella) (21), the potential in practical applications. Ideally, molecular field of synthetic molecular machines has evolved rap- motors can operate with high efficiency and durable idly in recent years. This is due to major advances in energy input (fuel), can be easily adapted to a specific supramolecular chemistry and nanoscience, the emer- environment or application, are compatible with spe- gence of the mechanical bond (7), and the develop- cific functions, and can be synchronized and act in ment of dynamic molecular systems (22). A variety of a cooperative manner. potential applications is now being considered in Where the pioneering work of Sauvage, Stoddart, areas ranging from catalysis (23) and self-assembly and others successfully led to stimuli-controlled trans- (24) to molecular electronics (25, 26) and responsive lational and rotary motion in mechanically interlocked materials (27, 28). Furthermore, translation of motion systems (1, 36–39), the induction of unidirectional ro- from the molecular scale to the macroscopic scale al- tary motion posed a major challenge. Distinct ap- lows for dynamically changing material properties proaches, including those based on catenanes (39), and the movement of larger objects. Cooperativity surface confined systems (40), and aryl–aryl single- and amplification across several length scales can be bond rotation (8, 41, 42), have been taken over the achieved, for example, by incorporating molecular last two decades to develop molecular motors capa- machines in gels (29, 30), liquid crystals (27, 31), and ble of such unidirectional rotation when supplied by polymers (32) or by anchoring them to surfaces (33, energy in the form of light, chemical stimuli, or elec- 34), allowing the control of a variety of properties in- trons (11). In this paper, we focus on rotary motors that cluding surface wettability (33, 34), contraction or contain a double-bond axle (Fig. 1). Although it may

aStratingh Institute for Chemistry, University of Groningen, 9747 AG Groningen, The Netherlands Author contributions: D.R., S.J.W., and B.L.F. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Published under the PNAS license. 1To whom correspondence may be addressed. Email: [email protected] or [email protected]. Published online April 30, 2018.

www.pnas.org/cgi/doi/10.1073/pnas.1712784115 PNAS | September 18, 2018 | vol. 115 | no. 38 | 9423–9431 Downloaded by guest on September 27, 2021 states, which are prone to such a thermal helix inversion (THI) process, have often been referred to as “unstable” or “meta- stable” states. The THI is energetically downhill and effectively withdraws the higher-energy isomer such as (M,M)-cis-1 from the photoequilibrium mixture and hence completes the unidirectional 180° rotary motion. The second part of the cycle proceeds in a similar fashion as a second photoisomerization step affords (M,M)-trans-1 (PSS trans to cis ratio of 90:10) with the methyl substituents again in the pseudoequatorial position. A second THI then reforms (P, P )-trans-1 and a full 360° rotation cycle is

Fig. 1. Schematic representation of unidirectional rotary motion completed. around a double-bond axle. The so-called second-generation light-driven molecular rotary motors, consisting of distinct upper (rotor) and lower (stator) halves and bearing only a single stereogenic center (Fig. 2C), were seem unusual to use a double bond as rotary axle since the rota- presented shortly after (47). Analogous to the first-generation tion is restricted, stimuli such as light can induce rotation (cf. isom- motors, 360° rotary motion can be achieved by a sequence of erization), as is most elegantly seen in the process of vision (43). As photochemical and thermal steps. The design, with nonidentical such, autonomous and repetitive unidirectional rotation has been halves, allowed for a much broader scope of functionalization, in successfully achieved in multiple systems, all of them driven by particular for surface anchoring through the stator, and paved the light. Here, we discuss the key design principles of these systems way for many different applications (12), as shown in Fig. 3. and furthermore a perspective on key challenges and possible future developments is provided.

Motors Based on Overcrowded Alkenes At the very basis of overcrowded alkene-based molecular motors is a photochemical cis–trans isomerization around their central carbon–carbon double bond. For stilbene, this process has been studied already for more than half a decade (44). Due to the symmetry of stilbene, there is no directional preference in the isomerization process. It was shown in 1977 that the introduction of steric bulk around the double bond distorts the otherwise planar geometry, giving rise to helical chirality (45). This feature was further exploited to develop a chiroptical switch, in which two pseudoenantiomeric forms with opposing helical chirality could be selectively addressed (46). This work formed the basis for the design and synthesis of the first molecule capable of undergoing unidirectional 360° rotation around a double bond, which our group reported in 1999 (9). It is based on an overcrowded alkene, with two identical halves on each side of the double bond (the rotary axle) [(P, P )-trans-1 in Fig. 2A]. Due to steric interactions between the two halves, in what is referred to as the fjord region, the molecule is twisted out of plane, resulting in a helical shape. The first molecular motor featured two stereogenic methyl substituents which are preferentially in a pseudoaxial orientation due to steric crowding. These stereocenters dictate the helical chirality in both halves of the molecule and hence the direction of rotation. A full rotary cycle consists of four distinct steps: two photochemical and energetically uphill steps and two thermally activated and energetically downhill steps. Starting from (P, P )-trans-1 (Fig. 2A), irradiation with UV light (>280 nm) induces a trans-to-cis isomerization around the double bond leading to isomer (M,M)-cis-1 with opposite helical chirality. This photoisomerization is reversible and under continuous irradiation a photostationary state (PSS) is observed in which for this particular case the ratio of cis to trans is 95:5. In (M,M)-cis-1 the methyl substituents end up in an energetically less favorable pseudoequatorial position. To release the built-up strain, a thermally activated process occurs, in which both halves slide along- side each other, inverting the helicity from left- (M,M) to right- Fig. 2. (A) Rotary cycle of a first-generation motor based on handed (P, P ) and allowing the methyl substituents to readopt overcrowded alkene. (B) Top view of the rotary cycle. (C) Structures the energetically favored pseudoaxial orientation. The photogenerated of second- and third-generation molecular motors.

9424 | www.pnas.org/cgi/doi/10.1073/pnas.1712784115 Roke et al. Downloaded by guest on September 27, 2021 For first-generation motors, the THI processes for unstable cis and trans isomers are different and therefore have different rates (9). Modifications to the design of the molecular motor can have complex and sometimes opposite effects on these rates. For example, the introduction of more steric bulk at the stereogenic center, by replacing the methyl substituent in motor 4 with an isopropyl group, accelerates the rate of thermal isomerization from the unstable to the stable cis form but decreases the rate going from the unstable to the stable trans isomer (Fig. 5) (54). The latter process was found to be so slow that an intermediate state could be observed with mixed helicity, that is (P, M )-trans-5, sug- gesting that the THI is a stepwise process. This kind of behavior was already predicted for related overcrowded alkenes that do Fig. 3. Molecular motors based on overcrowded alkene in different types of applications. not have stereogenic methyl substituents, which according to calculations racemize between (M,M) and (P, P ) helical structures via an intermediate structure with (P, M ) helicity (55). This example, The development of second-generation motors revealed that however, remains so far the only case in which such a stepwise the presence of only one stereogenic center is sufficient to induce mechanism for the THI in first-generation motors is observed. To unidirectional rotation. This raised the question of whether uni- decrease the amount of steric hindrance in the fjord region, and directional rotation can be achieved in the absence of any hence lower the energy barrier for THI, the central six-membered stereocenters (48). To address this question, symmetrical motors ring was changed to a five-membered ring (Motor 6 in Fig. 5) (56). were synthesized bearing two rotor units. These third-generation motors only have a pseudoasymmetric center and still unidirec- It has to be noted that upon reducing the ring size from six- to five- tional rotary motion around both axles was found to occur. membered, conformational flexibility is lost. As a consequence, Since our first reports on molecular rotary motors based on the unstable states are most likely further destabilized as the steric overcrowded alkene, great effort has been dedicated to the understanding of their functioning, especially the key parameters that govern the isomerization processes, and the use of new in- sights to adapt the structural design (11). This has resulted in a large collection of overcrowded alkene-based motors with different properties, which have been applied successfully to induce motion at the molecular scale as well as the nano scale and macro scale (27, 34, 49). The main aspects that have been investigated and that will be discussed in the next sections are the speed of rotation, the excitation wavelength, and the efficiency of the motors.

Rotational Speed Adjustment. For every different application of molecular motors, for example in soft materials or biological systems, often a distinct frequency of rotation is desired. The photochemical steps proceed on a timescale of picoseconds, making the usually much slower THI the rate-limiting step (50). Consid- erable research effort in our group has been devoted to fully understanding the THI and to altering the rotational speed by structural modifications. Throughout the years, density functional theory (DFT) calculations have proven to be useful in predicting thermal barriers before the synthesis of new motors and in inter- preting experimental results (51, 52). Although many factors may influence the rate of the THI, steric interactions within the molecule play a dominant role. Generally, two approaches have been taken to speed up the THI (Fig. 4): (i) by lowering the thermal barrier through a decrease in the steric hindrance in the fjord region or (ii) by raising the energy of the unstable state relative to the transition state. Additionally, electronic effects on the barrier of the THI were studied by introducing a strong push–pull system over the central double bond in a second-generation motor (53). A decrease in the barrier of the THI was observed as well as for the thermal E–Z isomerization. Consequently, upon generation of the Fig. 4. Approaches for speeding up the THI either through (i)a unstable state, both a “forward” THI and a competing “back- decrease in steric hindrance in the fjord region or (ii)by ” – – ward thermal E Z isomerization took place in this push pull destabilization of the unstable state with respect to the system, reducing the efficiency of the resulting motor. transition state.

Roke et al. PNAS | September 18, 2018 | vol. 115 | no. 38 | 9425 Downloaded by guest on September 27, 2021 that this decrease is due to destabilization of the unstable state, effectively lowering the barrier for THI. The speed of the rotary motors is also dependent on the solvent (65, 66). In a systematic study of motors with pending arms of varying flexibility and length it was established that solvent po- larity plays a minor role, but that in particular enhanced solvent viscosity for motor systems with rigid arms decreases THI drasti- cally (67). The results were analyzed in terms of a free volume model and it is evident that matrix effects (solution, surface, polymer, and liquid crystal) comprise a challenging multiparam- eter aspect in applying molecular motors. In all these examples, changing the speed of rotation of a molecular motor requires a redesign of the molecule and multistep synthesis. Dynamic control Fig. 5. Structural variations of first-generation molecular motors and of the rotational speed would be the next logical step in the de- effects on t1/2 of THI process. velopment of molecular motors. Locking the rotation by employing an acid–base-responsive self-complexing pseudorotaxane was the first example that allowed for such dynamic control over the hindrance cannot be relieved by folding, which additionally con- rotary motion (68). More recently, an allosteric approach was tributes to increased rates for the THI. reported in which metal complexation was used to alter the speed In an attempt to further destabilize the unstable states, over- of rotation (69). Complexation of different metals to the stator crowded alkene 7 was synthesized, which has two tert-butyl in- part of a second-generation molecular motor caused different de- stead of methyl substituents at the stereogenic center (57). grees of contraction of the lower half. As a consequence the steric However, these substituents cause too much steric hindrance hindranceinthefjord region decreased, which resulted in a lower impeding the unidirectional motion. Another approach is to re- barrier for the THI. place the naphthalene moieties with xylene moieties (motor 8) Precise control of the speed of rotation in a dynamic fashion (58). In this design, the xylyl methyl substituents cause the nec- remains challenging but the first examples have shown that essary steric hindrance in the fjord region. X-ray analysis shows lengthy syntheses can be avoided and motor speed can be al- that these methyl substituents are more sterically demanding in tered in situ. Controlling speed by external effectuators (metal/ion the trans isomer, forcing the molecule in a more strained confor- binding, pH, and redox) or tuning in response to chemical con- mation, also leading to destabilization of the unstable trans iso- versions (catalysis) or environmental (matrix and surface) constraints mer. The barrier of the THI from unstable trans to stable trans was offer exciting opportunities for more advanced motor functioning. found to be lower in motor 8 with respect to motor 6. However, the increased steric hindrance in the fjord region causes a higher Shifting the Excitation Wavelength. A major challenge in the barrier for the unstable cis to stable cis isomerization, reflecting field of photochemical switches and motors is to move away from the complex and opposite effect that (often subtle) changes in the the use of damaging UV light because it limits the practicality in molecular design may have on the rates of these two THI processes. soft materials and biomedical applications (70, 71). For this rea- Similar systematic structural modifications have been made to son, it is important to shift the irradiation wavelengths toward the second-generation motors to alter their speed of rotation. Initial visible spectrum (72). The most straightforward method is to make studies mainly involved motors of the general structure 9 (Fig. 6) in changes to the electronic properties of the motors in such a way which the bridging atoms (X and Y) were varied (47, 51, 52). Half- that the molecule is able to absorb visible light. However, such = = lives of the unstable states ranging from 233 h [X S, Y C(CH3)] changes may be detrimental to the photoisomerization process. = = to 0.67 h (X CH2,Y S) were measured. The conformationally The first successful example of a visible light-driven molecular flexible six-membered rings allow for the molecule to release motor made use of a push–pull system to red-shift the excitation some of the strain around the double bond that is built up in the wavelength (73). This second-generation motor comprised a nitro- photoisomerization step. DFT calculations have shown that, in acceptor and a dimethylamine-donor substituent in its lower half, case of a six-membered ring, the THI is a stepwise process and which allowed for photoexcitation with 425-nm light. An alternative multiple transition states have been identified (51, 52). strategy that is often used to red-shift the absorption of molecular Also here the change to a five-membered ring in the stator photoswitches relies on the extension of the π system. Indeed, upon makes the molecule more rigid. Again, this results in an increased extension of the aromatic system of the stator half of second- barrier for the THI in compound 10, up to the point where a generation motors unidirectional rotation could be induced by thermal E–Z isomerization becomes favored over the THI and a irradiation at wavelengths up to 490 nm (74). bistable switch is obtained (59). When only in the upper-half rotor Apart from these methods that focus on altering the highest a five-membered ring is introduced (motor 11), the rotational occupied molecular orbital– lowest unoccupied molecular orbital speed dramatically increases up to the megahertz regime (60). gap, alternative strategies based on metal complexes are highly Motor 12, bearing two five-membered rings, however, has a lower promising. For example, palladium tetraphenylporphyrin was barrier, in analogy to the first-generation motors, due to a de- used as a triplet sensitizer to drive the excitation of a molecular crease in the steric hindrance in the fjord region (61). The steric motor (75). Isomerization of the motor was shown to occur by hindrance, and as a consequence the THI barrier, was further re- triplet–triplet energy transfer, upon irradiation of the porphyrin duced by replacing the naphthalene moiety in the upper half with with 530- to-550 nm light. In a related example, a molecular motor xylene or benzothiophene (motor 13) (58, 62). Furthermore, larger was incorporated as a ligand in a ruthenium(II)–bipyridine com- substituents have been placed at the stereogenic center to in- plex (76). Irradiation with 450 nm into the metal-to-ligand charge crease the rate of the THI (63, 64) and DFT calculations showed transfer band resulted in unidirectional rotation.

9426 | www.pnas.org/cgi/doi/10.1073/pnas.1712784115 Roke et al. Downloaded by guest on September 27, 2021 Fig. 6. Structural variations of second-generation molecular motors.

These examples illustrate that there are multiple viable strat- bond (81–84). Solvent viscosity studies showed that this process is egies to red-shift the excitation wavelength of molecular motors. independent of solvent friction, which is consistent with a volume- However, the change of the wavelength region at which these conserving structural change (79, 85). The dark excited state, motors can be operated is still modest. Moving further away from formed after this first relaxation, has a lifetime of ∼1.6 ps and re- UV light toward red light or even near-IR remains a major chal- laxes back to the ground state to either the stable or unstable form lenge. There are several strategies that have shown promising via conical intersections (CIs). Relaxation to the ground state results for photoswitches, such as diarylethenes and azobenzenes, leaves excess vibrational energy which is dissipated to the solvent that have not been applied to molecular motors yet (72). For ex- at the tens of picoseconds timescale (81). The relatively long ample, multiphoton absorption processes using upconverting lifetime of the dark state is attributed to the fact that a high degree nanoparticles (77) or two-photon fluorophores (78) should be of twisting and pyramidalization of one of the carbons of the considered in future studies. central double bond is required to reach the CI (84). Recent studies showed that this relaxation to the ground state, which is Improvement of the Photochemical Efficiency. Improving the associated with twisting and pyramidalization, is not dependent on efficiency of the photochemical isomerization process has proven the size of the substituents (85), while it is dependent on viscosity. to be difficult as it not as well understood as the thermal isom- This observation suggests that the motion that accompanies the erization process. Typically, quantum yields below 2% are ob- relaxation to the ground state is not necessarily a complete rotation served for E/Z photoisomerization of second-generation motors (52, 79). To improve the yield, a detailed understanding of the of the halves but rather occurs only at the core of the molecule. The ability to control CIs could lead to major improvements, as excited state dynamics is required. Over the last decade, a com- bination of advanced spectroscopic studies and quantum chem- they play an important role in the efficiency of the photochemical ical calculations has been used to gain insight in the mechanism of step. To improve the efficiency of molecular motors, Filatov and the photochemical isomerization. Using time-resolved fluores- coworkers investigated the factors influencing the CIs in a theo- cence and picosecond transient absorption spectroscopy, a two- retical study (86, 87). The calculations predict that by placing step relaxation pathway was observed after the initial excitation electron withdrawing groups close to the central axle, such as an to the Franck–Condon excited state (50, 79, 80). Within 100 fs, a iminium, the character of the CI changes from a twist-pyramidalization bright (i.e., fluorescent) state relaxes to an equilibrium with a to a twist-bond length alteration. This effectively changes the lower-lying dark (i.e., nonfluorescent) state. Based on femtosec- mode of rotation from a precessional motion for current motors to ond stimulated Raman spectroscopy, supported by quantum an axial motion with higher efficiency. These computational de- chemical calculations, it has been postulated that this process is signs have already inspired the development of new photoswitches accompanied by elongation and weakening of the central double with increased efficiency (88) but have not yet been applied to

Fig. 7. Proposed rotational cycle for a redox-driven molecular motor.

Roke et al. PNAS | September 18, 2018 | vol. 115 | no. 38 | 9427 Downloaded by guest on September 27, 2021 here in the photochemical step, rather than the thermal isomerization step. Based on these design principles, Greb and Lehn (92) reported in 2014 on the synthesis of the first rotary motor based on imines (i.e., N-alkyl imine 14) bearing a stereocenter next to the central imine (Fig. 9). Because of the twisted shape of the lower half and E–Z isomerism of the imine four stereoisomers are formed. A helicity inversion does not occur under the experimental conditions due to the relatively high barrier for this process compared with the nitrogen inversion. Under thermodynamic equilibrium, there is a preference for (S,M)-cis over (S,P)-trans, whereas there is not a major preference for either (S,P)-cis or (S,M)-trans. Photochemical isomerization occurs upon irradiation with 254-nm light and at PSS the ratio is shifted toward (S,P)-trans relative to (S,M)-cis, while the ratio of the other two isomers remains unaffected by irradiation. Heating up the mixture of isomers to 60 °C for 15 h allows for the nitrogen inversion to occur, restoring the original distribution of diastereomers. Both processes are equilibrium reactions and therefore both forward and backward reactions can occur. However, due to preferred formation of one of the isomers in each step, overall a net Fig. 8. Proposed mechanism for an imine-based molecular motor. rotation occurs. During their investigations, it was found that annealing a benzene ring to the lower half is essential for this two-step motor motors and should be taken into account in attempts to increase as it effectively increases the thermodynamic barrier for the helicity the efficiency. inversion. Interestingly, when this inversion can occur, a molecular motor with a four-step rotary cycle is obtained, reminiscent of the Redox-Driven Motors. As an alternative to the use of (UV-visible) light to power molecular motors we considered designing an cycle for motors based on overcrowded alkenes. That is, two pho- electromotor taking advantage of redox processes. Preliminary tochemical isomerization steps and two thermally activated ring inversions give rise to 360° rotation. To show that imines can be studies toward using overcrowded alkenes as redox-driven mo- used as two-step molecular motors in a more general sense and to lecular motors are promising (89). A rotary cycle is envisioned, in provide more experimental and theoretical proof for the rotational which consecutive oxidation/reduction cycles would electro- behavior, camphorquinone imines were synthesized in a follow-up chemically form the unstable state, which then undergoes a THI to study (93). afford the stable state, completing 180° rotation (Fig. 7). Unfor- One of the major advantages of imine-based molecular motors tunately, the stereogenic center was found to be susceptible to is that many types of imines with different properties can be easily deprotonation, leading to an irreversible double-bond shift in synthesized through simple condensation reactions starting from which the central axis is converted to a single bond. As this type of commercially available materials. Furthermore, fine-tuning of the degradation pathway impedes any successful directional motion, speed of these motors can be achieved through controlling the a different design has to be made. Quaternization of the stereo- barrier for N-inversion. The barrier for this process depends genic center by replacing the hydrogen for a fluorine atom would prevent deprotonation. It was recently shown that such fluorine- substituted molecular motors with quaternary stereocenters are still capable of unidirectional rotation when irradiated by light, making them excellent candidates to be studied as redox-driven molecular motors (90).

Alternative Motor Designs In 2006, Lehn (91) proposed a new type of light-driven molecular motor derived from imines. The design is based on the two types of E/Z-isomerization processes that imines can undergo, namely a photochemical isomerization and a thermal nitrogen inversion. A two-step rotational cycle was proposed, starting with a light- induced E/Z isomerization, which has an out-of-plane rotational mechanism (Fig. 8). A thermally activated in-plane nitrogen inversion involves a planar transition state which would convert the system back to the original state. These two combined processes would lead to a net rotational motion as both follow a different pathway. Placing a stereogenic center next to the imine leads to preferential rotation by favoring the direction of the photochemical isomerization. This is different from the other examples of double-bond motors, as directionality is induced Fig. 9. A two-step molecular rotary motor based on imines.

9428 | www.pnas.org/cgi/doi/10.1073/pnas.1712784115 Roke et al. Downloaded by guest on September 27, 2021 was synthesized, which allowed for the direct observation of the fourth state (95).

Outlook Since the first development of light-driven molecular rotary motors two decades ago, great progress has been made in controlling unidirectional rotation around double bonds. In particular, the overcrowded alkene-based molecular rotary motors have been thoroughly investigated. Various designs are now increasingly applied to control dynamic functions (12); however, for a wider range of applications of these motors further improvements are essential (e.g., the use of longer irradiation wavelengths, as usually the photochemical isomerization steps are induced by UV light, which is harmful and thus impedes application in chemical biology and materials science). The first visible-light-driven motors that can be powered with light up to 500 nm have recently been introduced, but more powerful strategies such as multiphoton absorption or photon upconversion need to be explored since they will afford a major red shift in the irradiation wavelength, preferably even into the near-IR region. Although the influence of structural changes on the speed of rotation of these motors has been well established, Fig. 10. Rotational cycle for hemithioindigo-based motors. supramolecular and metal-based approaches that allow for speed adjustments with multiple stimuli are highly promising. Increasing the efficiency of molecular motors is a more complex largely on the substituent at the N-atom, providing a good handle problem that offers another nice challenge also in view of their to alter the speed of rotation. The assumption that there is a potential use in nanoscale energy conversion and storage as preferred direction of rotation in the photochemical E/Z isomeri- well as performance of mechanical work by future rotary motor- zation in chiral imines due to the unsymmetrical excited state based molecular machines. In this regard, theoretical studies surface is very plausible, but further experimental support to un- could aid at improving the efficiency and motor design. Another equivocally prove their preferred direction of rotation is warranted. major challenge for molecular motors that comprise a stereogenic These photoinduced isomerization processes often occur at the center is to obtain sufficient quantities of enantiopure material, picosecond timescale, making it very difficult to obtain direct which is needed to explore new applications, in particular to- evidence. Potentially, quantum mechanical calculations can aid in ward responsive materials. Enantioselective synthetic routes to- exploring the excited state surface. ward first- and second-generation motors have been recently In 2015, Dube and coworkers introduced a light-driven mo- developed (96, 97) and a chiral resolution method by crystalliza- lecular motor based on a thioindigo unit fused with a stilbene tion of first-generation motors offers important perspectives (98). fragment (Fig. 10) (94). The design and rotational cycle resemble All these fundamental challenges have to be considered in the that of the molecular motors based on overcrowded alkenes perspective of molecular machines: control of functions and the with the distinct difference that a sulfoxide stereogenic center is design of responsive materials. Tuning molecular motors to oper- present. Due to the steric crowding around the central axle, the ate in complex dynamic systems will require, among others, syn- substituents of the central double bond are twisted out of plane, chronization of rotary and translational motion, precise organization giving the molecule a helical shape. The helicity is dictated by and cooperativity, and amplification of motion along length scales. the chirality of the sulfoxide. The behavior of this motor was A first approach toward coupled motion was recently reported by examined by UV-visible and 1H-NMR spectroscopy, showing our group, in which the rotary motion of the molecular motor is that, in analogy to the overcrowded alkene motors, the rota- transferred to the synchronized movement of a connected biaryl tional cycle consists of four steps: two alternating sets of pho- rotor (99). The prospects for controlling motion at the nano scale tochemical and thermal isomerization steps. The photochemical and beyond will continue to provide fascinating challenges for the isomerization could be induced by light of wavelengths up to molecular designer and many bright roads for the molecular mo- 500 nm and a frequency of rotation of 1 kHz at room tempera- torist in the future. ture was determined. During the 1H-NMR studies, only the (E,S,M)-15 unstable state was observed, whereas the (Z,S,M)-15 Acknowledgments state could not be detected, presumably because the THI is too This work was supported by NanoNed, The Netherlands Organization for Scientific Research Top grant (to B.L.F.) and Veni Grant 722.014.006 (to S.J.W.), fast. This hypothesis was supported by detailed DFT calcula- the Royal Netherlands Academy of Arts and Sciences, the Ministry of Education, tions showing a four-step unidirectional rotary cycle. More re- Culture and Science (Gravitation programme 024.001.035), and European cently, a more sterically crowded and, therefore, slower motor Research Council Advanced Investigator Grant 694345 (to B.L.F.).

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