A Supercharged Molecular Motor Operating by Constitutional Alteration and Hydrogen Bonding

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Light driven variants stand out as particularly easy to fuel continuously and potentially carrying a very high energy content during their action. So far, such motors function via light induced bond rotations where the directionality is dictated by a fixed source of asymmetry within the structure. During the operation cycle there is no further structural change happening except for the rotation itself. In this work we disclose a hitherto unknown and highly effective mechanism for light driven motor rotation, which makes use of constitutional alteration of the structure. This in turn allows the directionality to be controlled actively by an intramolecular hydrogen bond instead of sterics. Associated with this unusual mechanism is a particularly high energy content that the motor retains from the incident light, which is of great importance for application of molecular motors working under external load. With these findings unique possibilities emerge for the design and use of molecular motors with unprecedented modes of action and power. Physical sciences/Chemistry/Organic chemistry Physical sciences/Chemistry/Photochemistry Physical sciences/Nanoscience and technology/Nanoscale devices/Molecular machines and motors Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Molecular motors have gained considerable traction as nanoscale powering units for advanced molecular machines and nanotechnology. 1–5 The central feature of molecular motors is their directional motions fueled by different sources of energy. 6 A variety of designs are available nowadays 7–14 and light powered versions stand out because of the straight forward and waste free energy supply (Fig. 1 a). 15–17 After Feringa and coworkers developed the first design of a working molecular motor in 1999, 18 different generations of the overcrowded alkene-based motors were brought forward by the same group. The difference between these generations lies in the number of stable stereogenic centers (two for generation I, 18 one for generation II, 19 and only a pseudo-chiral center in generation III 20 ), which provide permanent asymmetry to the molecular structures. A source of permanent asymmetry is necessary to control directionality of the motors. The common working mechanism of Feringa-type motors is comprised of two photoisomerization steps, which are intersected by two ratcheting thermal helix inversion (THI) steps. A number of alternative designs for light driven molecular motors have been developed and experimentally proven since. In 2014 Greb and Lehn developed an imine-based molecular motor system, in which thermal ratcheting steps are imine-inversion or ring-flip processes instead of THI. 21, 22 Again, a carbon-based stereocenter bearing differently sized groups serves as source of asymmetry. In 2015 our group presented a hemithioindigo (HTI)-based molecular motor, which can be powered by visible light and works by a closely related mechanism to the Feringa motors. 23–25 In 2018 we established the first photon-only molecular motor, which does not require thermal steps in its working mechanism but functions by three consecutive irradiation steps. 26 This different mechanism leads to unique properties, for example the motor becomes faster and more efficient with decreasing temperature. One year later we reported on yet a different type of molecular motor, which performs a directional figure of eight shaped motion instead of the hitherto possible circular motions. 27 The working mechanism of the latter involves thermal hula-twist isomerizations as ratcheting steps instead of THIs, i.e. the synchronized rotation of the central double bond and a directly adjacent single bond. Further designs have emerged since, including biomimetic artificial motors 28, 29 and a number of theoretically predicted versions. 30–37 In principle it is possible to imagine other sources of directionality control in light-driven molecular motors and weak interactions have been discussed for some time in this regard. In particular hydrogen bonding was identified in a theoretical study as early as 2013 by the groups of Sampedro and Frutos to be a very interesting candidate for controlling directionality. 38 Related endeavors have put forward supramolecular hydrogen bonding interactions to remote-control the directionality of the motor. 39, 40 Most recently a molecular motor with intramolecular hydrogen bonding was disclosed by Crespi and Feringa using a chiral hydroxy-indanone rotor and a barbituric acid stator part. 41 Here the source of asymmetry is the hydroxy-bearing stereocenter adjacent to the rotating central double bond, which forms a hydrogen bond to the stator carbonyl function. This places the intramolecular hydrogen bonding in an ideal position to influence the rotation process. The described working mechanism encompasses again four steps, two light induced double-bond isomerizations and two intersecting thermal helix inversions, similar to the working mechanism of the original Feringa motor. In this work we present a molecular motor setup 1 employing a similar intramolecular hydrogen bonding interaction to control the light-powered unidirectional rotation process (Fig. 1 b). However, different to all earlier described molecular motor mechanisms, we found that motor 1 undergoes a five-step motion cycle involving a hitherto unprecedented constitutional alteration and subsequent hydrogen-bond directed rotation. In this process light induced double bond isomerization is tied to intramolecular epoxide formation and proton transfer producing a high-energy intermediate, which stores a substantial amount of the incident light energy. The conformation of the epoxide structure, and hence the rotary state of the motor, is held in place by intramolecular hydrogen bonding with inverted donor and acceptor, which fully determines the directionality of the rotation. A follow-up thermal step opens up the epoxide and restores the original constitution of the motor while quantitatively ratcheting the directional motion. For the remaining two steps in the motor mechanism the expected light induced double bond isomerization and thermal helix inversion are observed without constitutional alteration. This unique motor mechanism provides unprecedented opportunities, especially for harnessing much more energy of the incident light within the course of the directional rotation. Taken together our findings open the door to a fully unknown mechanistic realm for creating and controlling directional motions at the smallest scales. They thus provide unique opportunities for designing and applying light-driven molecular motors with strongly enhanced power for a next generation of molecular machines. Results and Discussion So far, the source of asymmetry in all HTI-based molecular motors is a sulfoxide with point chirality instead of a carbon stereogenic center to control directionality. 23–27, 42, 43 For HTI motor 1 , we have now changed the asymmetry source to a carbon based stereocenter, which resides on the indanone- in place of the thioindigo fragment. This stereogenic center invokes an alcohol moiety in close proximity to the central double bond – the axis of directional rotation – which can form an intramolecular hydrogen bond to the stator fragment. The sulfur atom at the thioindigo fragment is not oxidized, which is expected to lead to a notable red-shift of the absorption of the motor as compared to the related structural setup of first generation HTI-based motors. A bromide is introduced at the thioindigo fragment for the dual purpose of facilitating synthesis (as halogenated benzothiophenones are more stable and less prone to form thioindigo as side product) and to introduce a convenient handle for late-stage functionalization and applications. A theoretical analysis on the DFT level of theory was conducted first to elucidate the motor rotation mechanism of 1 . A direct comparison was made to the behavior of ether-derivative 2 lacking hydrogen bonding capacity. For clarity only structures with ( R )-configured stereocenter are considered in the following. The theoretical description of 1 reveals a very unusual yet very well-suited energy surface for proper unidirectional light powered motor rotation (Fig. 2 ). The global minimum structure A - 1 possesses E configuration of the central double bond and allows intramolecular hydrogen bonding between the hydroxy group and the carbonyl function of the thioindigo fragment. A ( P )-helicity is adopted in this structure, which brings the larger i -propyl substituent at the stereogenic center to the same side as the methoxy-group in ortho -position with regard to the double bond. With the helicity already hinting at the rotation direction, photoisomerization in a counterclockwise manner would lead to population of isomer B - 1 with Z configured double bond and ( M )-helicity. Now the hydroxy group at the stereocenter and the ortho -methoxy group are placed at the same side of the molecule. During this photoconversion intramolecular hydrogen bonding with the carbonyl is disrupted. In the calculation no significant hydrogen bonding interaction between the hydroxy group as donor and the sulfur atom as acceptor are found. A chalcogen bonding interaction between the sulfur and the carbonyl oxygen, as recently observed in heterocylic HTI photoswitches, 44 is also not likely in this case (see Supporting Information for details). Isomer B - 1 possesses a very high energy of 7.55 kcal/mol according to theory and stabilizes in a thermal step by inverting helicity. This helix inversion continues the directional rotation and serves as ratcheting step in the motor mechanism. A transition state with 9.6 kcal/mol elevated energy is predicted for this process. As a result, isomer C - 1 with Z -configuration of the double bond and ( P )-helicity is formed. The energy of isomer C - 1 is predicted to be lowered by 4.43 kcal/mol as compared to B - 1 , which leads to complete conversion at ambient to high temperatures. Still, the stabilized isomer C - 1 possesses a significantly higher energy than the global minimum by 3.7 kcal/mol. Taken together, these values belong to the highest amounts of photoenergy being stored in metastable HTI switches and motor systems so far. The significant energy content would lead to a complete thermal conversion from C - 1 to isomer A - 1 at elevated temperatures. The sequence of isomer interconversions from A to B to C represents the first 180° unidirectional rotation of motor 1 . We expected a similar two-step interconversion between three isomers for the second 180° rotation instead of the population of an additionally and highly unusual epoxide-intermediate D - 1 . Photoirradiation of C - 1 would thus continue rotation in a counterclockwise sense leading to population of metastable isomer E - 1 with E -configured double bond and ( M )-helicity. Intramolecular hydrogen bonding would be reestablished in this step with the carbonyl as acceptor. In E - 1 again the smaller hydroxy group at the stereocenter and the ortho -methoxy group are located on the same side of the molecule. Isomer E - 1 is calculated to be 2.3 kcal/mol higher in energy compared to A - 1 and could thus be converted completely into the latter by another thermal helix inversion step. However, we found in the calculations, that in this process intramolecular hydrogen bonding is retained and the predicted transition state is only 1.8 kcal/mol higher in energy. With such low transition state energy an experimental observation of the thermal E - 1 to A - 1 conversion would not be possible without resorting to ultrafast transient spectroscopy methods. In contradiction to this initial theoretical assessment, we found a conveniently stable intermediate experimentally, which decayed completely into A - 1 with an associated Gibbs energy of activation of 13.0 kcal/mol. Since also experimental spectroscopy evidences (see below) and theoretical spectra did not match for the expected isomer E - 1 , we returned to a more comprehensive theoretical assessment. Two options were taken into account guided by the experimental observation that UV/vis absorption is strongly hypsochromically shifted. To explain this behavior we assumed that conjugation via the central double bond is broken in the experimentally observed intermediate and either an epoxide or a furane-based structure is formed. As is described in more detail in the Supporting Information, the calculated epoxide structure D - 1 matches very well both energetically and spectroscopically with the experimentally observed intermediate. D - 1 is formed by a conjugated intramolecular epoxidation reaction while at the same time the hydrogen bond donor shifts to the former carbonyl – and now enol - site of the thioindigo fragment. A strong intramolecular hydrogen bond is formed between the enol and the epoxide, locking the structure in a nearly perpendicular arrangement of the indanone rotor versus the thioindigo stator. D - 1 thus represents a “trapped” 90° rotation intermediate possessing an exceptional high energy of 12 kcal/mol. This large portion of energy is directly stored from the incident light irradiation and could thus be expended to do actual work in the thermally activated follow up steps. It establishes an unprecedented supercharging of a light-driven molecular motor. The next thermally activated step is calculated to be an epoxide opening and proton transfer step, which is tied to further rotation to reach intermediate E - 1 . The initial rotation direction is maintained in this step and a considerable Gibbs energy of activation of 14.9 kcal/mol is predicted. The final E - 1 to A - 1 thermal helix inversion step was found in the initial calculations as described above. With the theoretically predicted energy profile a quantitative directionality is expected for motor 1 even at higher temperatures. Low temperature experiments should allow to observe four different isomers A - 1 , B - 1 , C - 1 , and D - 1 and thus evidence unidirectionality directly. To complete the theoretical analysis NMR, UV/vis as well as ECD spectra were calculated at the CAM-B3LYP/6-311G(d,p) level of theory and the effect of different solvents (THF or Et 2 O) were included through the polarizable continuum model (PCM) (see Supporting Information for details). The hydroxy group proton signal in the 1 H NMR spectrum was found to be especially sensitive to the particular isomeric state and thus was predicted to be a powerful probe for conformational analysis. UV/vis spectra report on significant electronic changes such as E or Z configuration of the central double bond and especially its braking during the constitutional alteration step. Electronic circular dichroism (ECD) spectra are highly sensitive to the particular helicity of the isomers, which would complete an unambiguous assignment of spectral species in the experiments. A similar theoretical analysis was conducted for methoxy-substituted derivative 2 lacking the capacity for intramolecular hydrogen bonding. In this case the energy profile reveals that compound 2 also is a motor but adheres to the classical four-step cycle (including states A - 2 , B - 2 , C - 2 , and E - 2 ) with alternating photochemical and thermal helix inversion steps. The sense of directionality is the same as in motor 1 , which directly shows that hydrogen bonding in this classical rotation mechanism is not responsible for unidirectionality. Additionally, the C - 2 isomer is now the global minimum and significantly less energy is stored in the metastable states B - 2 (3.13 kcal/mol) and E - 2 (4.84 kcal/mol). With this energy profile full unidirectionality would still be present, as the thermal helix inversion steps from B - 2 to C - 2 and E - 2 to A - 2 still lead to complete conversions and thus to effective ratcheting. Like for 1 the most stable structures A - 2 and C - 2 feature a syn -relation of the large i -propyl group and the aromatic methoxy group in ortho -position to the central double bond at the five membered indanone ring. It thus becomes clear that the size differences at the stereogenic center are primarily responsible for dictating the sense of directionality. Synthesis of motor 1 is described in detail in the Supporting Information and starts from commercially available 3-(2,5-dimethoxyphenyl)propanoic acid ( 3 ). After intramolecular Friedel-Crafts acylation the corresponding 4,7-dimethoxy-indanone ( 4 ) is obtained to which the i -propyl group was introduced via alpha-deprotonation and substitution with i -propyl iodide. The resulting indanone 5 was obtained in 31% yield. To our surprise prolonged treatment of 5 with base led to formation of the alpha-hydroxylated indanone 6 . A similar reaction has been reported just when writing this manuscript by Crespi, Feringa, and co-workers under Lewis-acid conditions, 41 which we were not aware of at the time when synthesizing our motor. After optimization a satisfactory yield of 60% was achieved when bubbling air through the solution to increase the dioxygen reactant level. A future closer examination of this reaction will reveal details about the mechanism and probe its scope, however it is already evident that the hydroxy group stems from the air’s dioxygen. Condensation of indanone 6 and benzothiophenone 7 in the presence of BCl 3 gave the final motor 1 in 23% yield. Single crystals suitable for X-ray analysis could be obtained for the two stable isomers, the global minimum E -isomeric A - 1 as well as for metastable Z -isomeric C - 1 , directly evidencing the molecular structure and intramolecular hydrogen bonding in A - 1 (Fig. 3 a). Deuteration experiments allowed to identify the 1 H NMR signals of the OH proton in the different isomers of motor 1 directly (Fig. 3 b). After successful synthesis the thermal behavior of motor 1 was scrutinized first. At ambient temperature only two isomers could be observed and fully characterized, A - 1 and C - 1 , as predicted by theory. The metastable isomer C - 1 was isolated after irradiation of A - 1 with 450 nm light and flash column chromatography separation of the two isomers. Upon prolonged heating to 50°C in CDCl 3 solution C - 1 is completely converted into A - 1 . When conservatively assuming that remaining 5% of C - 1 cannot be observed in the 1 H NMR experiment, the resulting equilibrium constant K = 95/5 at 50°C can then be translated into the corresponding Gibbs energy difference between A - 1 and C - 1 Δ G = 1.9 kcal/mol. This value is the lower limit of the energy difference between the two isomers and thus the theoretically predicted value of 4.86 kcal/mol difference is supported by experiment. A corresponding Gibbs energy of activation of Δ G ‡ = 25 kcal/mol was determined from kinetic analysis of the thermal C - 1 to A - 1 conversion. Next irradiation experiments were conducted at low temperatures to evidence the direct photoproducts formed upon irradiation of A - 1 and C - 1 . Starting from A - 1 , in situ irradiation at − 130°C in a 1:1 mixture of THF- d 8 : CS 2 revealed the formation of one new isomer as the direct photoproduct first and subsequently formation of isomer C - 1 as well (Fig. 3 c). The isomer populated first could not be accumulated strongly even at the low temperature but quickly reached a steady state concentration while the population of C - 1 further increased upon continued irradiation. When switching off the light and raising the temperature slightly to − 125°C, the first formed isomer thermally converted exclusively into C - 1 (Fig. 3 d). The kinetic analysis delivered a Gibbs energy of activation of Δ G ‡ = 9.67 kcal/mol for this process (see Supporting Information for details). This behavior is fully consistent with the predicted properties of isomer B - 1 , which could thus be assigned as the direct photoproduct of A - 1 . A complementary set of experiments was conducted to investigate the photoisomerization of isomer C - 1 . To our surprise irradiation of C - 1 at − 105°C in THF- d 8 solution resulted in the population of a fourth isomer, which could be accumulated almost quantitatively (Fig. 3 e). This strong accumulation allowed a thorough 1 H NMR analysis at low temperatures (–108°C to − 120°C) including NOE experiments to evidence the E configuration of the (supposed to be intact) double bond (see Supporting Information for all details of this analysis). However, upon closer scrutiny, 2D NMR analysis revealed that no carbonyl-carbon signal could be detected. Further, signal shifts of the expected central double bond-carbon atoms as well as the stereogenic carbon center also did not match with their expected hybridization or substitution-character. Thermal annealing of the new isomer at − 80°C in the dark led to full conversion to A - 1 (Fig. 3 f). The corresponding kinetic analysis revealed a Gibbs energy of activation of Δ G ‡ = 13 kcal/mol for this process, which is in stark contrast to the expected barrier for thermal E - 1 to A - 1 conversion. Because of these accumulated experimental evidences and discrepancy to the calculations it became clear that this fourth isomer could not be E - 1 . However, remarkably good agreement between theoretically calculated and experimental NMR spectra were found for the epoxide constitutional isomer D - 1 (see below). Moreover, also the calculated Gibbs energy of activation for thermal D - 1 to E - 1 conversion matches very well with the experimentally established value for the intermediate decay. In order to fully support the tentative isomer assignment of the intermediate to D - 1 as well as assignments of the other isomers, theoretically predicted NMR, UV/vis, and ECD spectra were compared to experimental ones (see Fig. 4 and the Supporting Information for more details). The theoretically predicted 1 H NMR chemical shifts are in very good agreement with the experiments under the assumption that the photoproduct of C - 1 irradiation is indeed D - 1 (see Supporting Information for the detailed comparison of experimental and theoretical D - 1 spectra). UV/vis spectra and ECD spectra of A - 1 , B - 1 , C - 1 , and D - 1 could be directly compared between low temperature experiment and theory and again a very good agreement was found (Fig. 4 a-d). To this end EPA (5:5:2 mixture of Et 2 O: i -pentane: EtOH) was used as solvent to access very low temperatures, which allowed to obtain the UV/vis and ECD spectra for the pure D - 1 isomer at − 120°C and even the full spectral signature of the fleeting B - 1 isomer at − 160°C. When irradiating enantiomerically pure A - 1 at − 160°C the UV/vis spectrum displayed a bathochromic shift, while the ECD spectrum changed signs of the Cotton effect (Fig. 4 e). This behavior reveals first, that the conjugation of the central double bond is not broken in the intermediate and second, that it possesses opposite helicity. Further the bathochromic absorption shift is indicative for a change from E to Z configuration of the central double bond similar to HTI photoswitches in general (note that in HTIs the E and Z nomenclature appears inverted because of the particular substitution pattern and resulting CIP priorities of 1 ). A very good match with the calculated UV/vis and ECD spectra of B - 1 is observed in this case, which thus could confidently be assigned (Fig. 4 b). Thermal annealing at − 108°C led to the known spectra of C - 1 (Fig. 4 e) directly reporting on full unidirectionality for the whole A - 1 to B - 1 to C - 1 conversion sequence. When irradiating enantiomerically pure C - 1 at − 120°C a very distinct behavior was observed (Fig. 4 f). A new intermediate state formed with strongly hypsochromically shifted absorption. In fact, no absorption in the visible range remained after full conversion in the pss, which directly evidences breaking of the central double bond and thus loss of conjugation in the intermediate isomer. Besides the UV/vis absorption also the corresponding ECD spectrum could very well be matched with the theoretically predicted one of intermediate D - 1 (Fig. 4 d), which allowed us to now unambiguously assign this isomer. It was thus found that a highly unusual constitutional alteration takes place in the photochemical C - 1 to D - 1 transition, which retains a large amount of the incident lights energy according to the theoretical description. Thermal annealing at − 80°C led to full conversion to the A - 1 isomer as evidenced by both UV/vis and ECD spectral changes without the observable formation of state E - 1 (Fig. 4 f). This behavior is expected from the very small calculated Gibbs energy of activation for the THI, which leads from E - 1 to A - 1 . Therefore, D - 1 seems to directly convert to A - 1 at the temperature of the experiment but does in fact undergo first epoxide ring opening to E - 1 and then quick follow-up THI to A - 1 , which cannot be evidenced individually by experiment. Overall, the combined NMR, UV/vis and ECD experiments allowed an unambiguous isomer assignment confirming constitutional alteration as a key-step as well as complete unidirectionality of motor 1 . Especially noteworthy is the completely selective conversion of D - 1 to E - 1 and then to A - 1 , since isomer D - 1 inherits a single bond instead of the configurationally stable double bond as rotation axis. It is only because of the significant intramolecular hydrogen bond that the rotation direction is not reversed in the thermal follow up step, which would populate C - 1 instead E - 1 . Our calculations show that D - 1 is the global minimum of the epoxide state, which is not the case when the OH proton is replaced by a methyl group in silico (see Supporting Information for the corresponding data). The hydrogen bonding effect is present even in protic solvents like MeOD- d 4 (see below and the Supporting Information) and despite an apparent proton-deuterium exchange. Thus, intramolecular hydrogen bonding is truly dictating the sense of directionality in the D - 1 to A - 1 rotation sequence and thus is responsible for motion control instead of sterics. Interestingly this is not the case for the A - 1 to B-1 to C - 1 rotation sequence, although intramolecular hydrogen bonding is present in isomer A - 1 and needs to be broken in the photochemical step. However, we found that when the OH proton is replaced again by a methyl group in silico , the inherent directionality of the corresponding A - 2 to B-2 to C - 2 rotation sequence is retained and thus is the same as in motor 1 . It becomes apparent that isomers A are more stable than isomers B within this molecular setup in general, which is a steric effect that favors the i -propyl group residing at the same side of the indanone plane as the phenyl-methoxy (see the Supporting Information for more details). When comparing the kinetics for the thermal helix inversion from D - 1 to A - 1 (both intramolecularly hydrogen bonded) no strong influence of the solvent polarity was observed. Kinetic analysis in MeOH or THF delivered roughly the same Gibbs energy of activation of Δ G ‡ = 13 kcal/mol for this process (see Supporting Information). It has to be emphasized however, that for this process no full disruption of the intramolecular hydrogen bond is needed for the conversion from D - 1 to A - 1 but rather a proton hopping during re-tautomerization and epoxide opening. Therefore, possible effects of the solvent are likely to cancel out rather than preferring one isomeric state and significantly altering the energy landscape. It finally needs to be emphasized that a significant red shift of about 50 nm is seen for the absorptions of the stable A - 1 and C - 1 isomers when compared to the structurally related first HTI motor inheriting a sulfoxide as stereogenic center. Such red shift of absorption is desirable for many applications of molecular motors e.g. in the context of biology, catalysis, or materials and thus makes motor 1 a highly interesting candidate in this regard. In conclusion, we describe a HTI-based light driven molecular motor 1 inheriting intramolecular hydrogen bonding. Different to all earlier HTI-motor setups, motor 1 receives its asymmetry from a carbon-based stereogenic center located at the indanone fragment. We demonstrate that this asymmetry is effectively translated into complete unidirectionality of the motor rotation. We further evidence that hydrogen bonding is in fact responsible for unidirectionality of this motor. A unique and distinct operation mechanism is established in which constitutional alteration and tautomerization processes allow to store an unprecedented large amount of the provided light energy within the motor rotation cycle. With this molecular setup a new type of molecular motors has become available that can be supercharged by light irradiation. This progress will open up an unexplored realm of motor applications where a significant energy budget or workload is expended e.g. in active mechanically driven processes 45–50 or bulk material changes. 51–55 Declarations Acknowledgements H. Dube thanks the Deutsche Forschungsgemeinschaft (DFG) for an Emmy Noether fellowship (DU 1414/1-2). A. Ozcelik thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship. We further thank C. Placht for considerable help with NMR measurements at variable temperatures. Author Contributions Statement H.D., P.K.B. and A.O. conceived and designed the project. P.K.B. synthesized and characterized all compounds, crystallized C - 1 for X-ray analysis, and conducted the initial thermal and photochemical measurements as well as data analysis. A.O. purified and isolated different isomers, crystallized A - 1 for X-ray analysis, characterized D - 1 , conducted the in depth thermal and photochemical measurements as well as data analyses, and provided the initial quantum chemical description. M.H. provided the in-depth quantum chemical characterization of the motor. H.D. wrote the paper and edited the Supplementary Information. All contributors discussed, edited, and refined the work and the written manuscript and Supplementary Information. Competing Interests Statement The authors declare no competing interests. References Costil, R.; Holzheimer, M.; Crespi, S.; Simeth, N. A.; Feringa, B. L., Directing Coupled Motion with Light: A Key Step Toward Machine-Like Function. Chem. Rev. 2021, 121 (21), 13213-13237. Krause, S.; Feringa, B. L., Towards artificial molecular factories from framework-embedded molecular machines. Nat. Rev. Chem. 2020, 4 (10), 550-562. Kay, E. R.; Leigh, D. 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L.; Morsa, D.; de Boer, J.; Pacella, G.; van den Enk, T.; Kobauri, P.; Portale, G.; Schalley, C. A.; Feringa, B. L., A light-fuelled nanoratchet shifts a coupled chemical equilibrium. Nat. Nanotechnol. 2022, 17 , 159-165. Gao, C.; Vargas Jentzsch, A.; Moulin, E.; Giuseppone, N., Light-Driven Molecular Whirligig. J. Am. Chem. Soc. 2022, 144 (22), 9845-9852. Regen-Pregizer, B. L.; Dube, H., Defining Unidirectional Motions and Structural Reconfiguration in a Macrocyclic Molecular Motor. J. Am. Chem. Soc. 2023, 145 (24), 13081-13088. Orlova, T.; Lancia, F.; Loussert, C.; Iamsaard, S.; Katsonis, N.; Brasselet, E., Revolving supramolecular chiral structures powered by light in nanomotor-doped liquid crystals. Nat. Nanotechnol. 2018, 13 , 304-308. Chen, J.; Leung, F. K.; Stuart, M. C. A.; Kajitani, T.; Fukushima, T.; van der Giessen, E.; Feringa, B. L., Artificial muscle-like function from hierarchical supramolecular assembly of photoresponsive molecular motors. Nat. Chem. 2018, 10 (2), 132-138. Ryabchun, A.; Lancia, F.; Chen, J.; Plamont, R.; Morozov, D.; Feringa, B. L.; Katsonis, N., Macroscopic motion from synchronized molecular power strokes. Chem . Li, Q.; Fuks, G.; Moulin, E.; Maaloum, M.; Rawiso, M.; Kulic, I.; Foy, J. T.; Giuseppone, N., Macroscopic contraction of a gel induced by the integrated motion of light-driven molecular motors. Nat. Nanotechnol. 2015, 10 , 161-165. Foy, J. T.; Li, Q.; Goujon, A.; Colard-Itte, J.-R.; Fuks, G.; Moulin, E.; Schiffmann, O.; Dattler, D.; Funeriu, D. P.; Giuseppone, N., Dual-light control of nanomachines that integrate motor and modulator subunits. Nat. Nanotechnol. 2017, 12 , 540-545. Additional Declarations There is NO Competing Interest. Supplementary Files 22DubPB01RCCDC2307158.cif Supplementary Data Set 1 23DubAO01CCDC2307157.cif Supplementary Data Set 2 BiswasOzcelikDubeSI.pdf Supplementary Information Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3660237","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":272614253,"identity":"a3ef9450-0b83-437a-84af-127b135495de","order_by":0,"name":"Henry Dube","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACAwjFDGQwH/gAZDE2kKCFLXEGqVp4DInTYs7ee+wzD4N14nb2no8NP9sYZPsJabHsOZc8m4chPXFnz9mNjb1tDMYzCVljcCPHmJmH4XDihhu52x/wtjEkbjhASMv9N1At9988bPwL1LKfoJYbPDBbeBibwbYQ8ovBmRxjxjkG6cY7e9IMm2XOSRjPIGjL8TPGDG8qrGW3sx9+2PimzEa2v4GQNUDAxGMAZ0sQoR4IGH8Qp24UjIJRMApGKgAAWcZDi9ZQ0j4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5055-9924","institution":"Friedrich-Alexander University Erlangen-N\u0026#x00FC","correspondingAuthor":true,"prefix":"","firstName":"Henry","middleName":"","lastName":"Dube","suffix":""},{"id":272614254,"identity":"e21faa0c-aa85-4a5d-9e82-34e41af7fddb","order_by":1,"name":"Pronay Biswas","email":"","orcid":"","institution":"Friedrich-Alexander University Erlangen-Nü","correspondingAuthor":false,"prefix":"","firstName":"Pronay","middleName":"","lastName":"Biswas","suffix":""},{"id":272614255,"identity":"22d14eb2-76a8-45a3-8afc-c8083872113e","order_by":2,"name":"Ani Ozcelik","email":"","orcid":"","institution":"Friedrich-Alexander University Erlangen-Nü","correspondingAuthor":false,"prefix":"","firstName":"Ani","middleName":"","lastName":"Ozcelik","suffix":""},{"id":272614256,"identity":"08c23198-82de-473d-a6af-9a257c703816","order_by":3,"name":"Martina Hartinger","email":"","orcid":"https://orcid.org/0009-0009-5827-0226","institution":"Friedrich-Alexander University Erlangen-Nü","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Hartinger","suffix":""},{"id":272614257,"identity":"b45fedff-7354-4412-8af6-b28316bebfef","order_by":4,"name":"Frank Hampel","email":"","orcid":"","institution":"Friedrich-Alexander-Universität Erlangen-Nürnberg","correspondingAuthor":false,"prefix":"","firstName":"Frank","middleName":"","lastName":"Hampel","suffix":""}],"badges":[],"createdAt":"2023-11-24 17:00:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3660237/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3660237/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51137060,"identity":"9ba68b11-be58-4311-96d6-92cea73e50ab","added_by":"auto","created_at":"2024-02-14 18:39:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":330590,"visible":true,"origin":"","legend":"\u003cp\u003eLight powered molecular motors and their mechanism of action. a) Typical working mechanism of a light driven molecular rotary motor with alternating photoisomerization and thermal helix inversion steps. Directionality is controlled by the sterics of a permanent stereochemical element and the structure remains constitutionally unaltered. The example given represents a second generation Feringa motor. b) HTI-based molecular motor \u003cstrong\u003e1\u003c/strong\u003e invoking constitutional alterations during rotation and hydrogen bonding controlled unidirectionality. The constitutional isomer (framed) represents a high energy intermediate for storing a large amount of the introduced light energy.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/af0deb040e2736729dd052c4.png"},{"id":51137064,"identity":"e1ceaa0e-d381-43fe-9789-80e5a367ea5c","added_by":"auto","created_at":"2024-02-14 18:39:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":217143,"visible":true,"origin":"","legend":"\u003cp\u003eTheoretical description of hydrogen bonded molecular motor \u003cstrong\u003e1\u003c/strong\u003e (\u003cstrong\u003ea\u003c/strong\u003e) and methoxy-derivative \u003cstrong\u003e2\u003c/strong\u003e (\u003cstrong\u003eb\u003c/strong\u003e) without the capacity for intramolecular hydrogen bonding calculated at the CAM-B3LYP/6-311G(d,p)/PCM(THF) level of theory. Experimentally determined Gibbs energies of activation for the \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1 \u003c/strong\u003eto \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (measured at –125 °C) and \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1 \u003c/strong\u003e(measured at –80 °C and monitored by the disappearance of \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e) transitions are shown as red numbers for comparison.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/ef551fbc395b2d6e09e4adfd.png"},{"id":51137062,"identity":"103230c6-27a7-48d0-8e26-b3b6b5b267ab","added_by":"auto","created_at":"2024-02-14 18:39:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":541351,"visible":true,"origin":"","legend":"\u003cp\u003eSingle crystal structures and \u003csup\u003e1\u003c/sup\u003eH NMR (400 MHz) spectroscopic analysis of motor \u003cstrong\u003e1\u003c/strong\u003e. a) ORTEP presentations of the \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e structures in the crystalline state. b) Partial \u003csup\u003e1\u003c/sup\u003eH NMR spectra (THF-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e8 \u003c/sub\u003e: CS\u003csub\u003e2\u003c/sub\u003e 1 : 1 for spectra 1-3 from the top or MeOD\u003cem\u003e d\u003c/em\u003e\u003csub\u003e4\u003c/sub\u003e for spectrum 4) of isomeric mixtures of motor \u003cstrong\u003e1\u003c/strong\u003e recorded before and after deuterium exchange with MeOD-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e4\u003c/sub\u003e. c) Partial \u003csup\u003e1\u003c/sup\u003eH NMR spectra (THF-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e8 \u003c/sub\u003e: CS\u003csub\u003e2\u003c/sub\u003e 1 : 1) recorded at –130 °C during \u003cem\u003ein situ \u003c/em\u003eirradiation of \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e leading to photoconversion to \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. d) At –125 °C \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e quickly and exclusively converts to \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e in a thermally activated process in the dark. e) Partial \u003csup\u003e1\u003c/sup\u003eH NMR spectra (THF-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e8\u003c/sub\u003e) recorded at –108 °C during \u003cem\u003ein situ \u003c/em\u003eirradiation of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e leading to photoconversion to \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. f) At –80 °C \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e converts exclusively to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e in a thermally activated process in the dark.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/f1dc10df5142ef81b9ed4760.png"},{"id":51137065,"identity":"71759ddd-e9fc-4ffb-b299-a9cee9e4432b","added_by":"auto","created_at":"2024-02-14 18:39:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":270527,"visible":true,"origin":"","legend":"\u003cp\u003eUV/vis and ECD spectroscopic analysis of molecular motor \u003cstrong\u003e1\u003c/strong\u003e. Experimental spectra recorded in EPA at low temperatures (colored lines) and calculated (CAM-B3LYP/6-311G(d,p)/PCM(Et\u003csub\u003e2\u003c/sub\u003eO) level of theory, black lines) spectra are shown together for motor \u003cstrong\u003e1\u003c/strong\u003e isomers with (\u003cem\u003eR\u003c/em\u003e)-configured stereocenter. Theoretically obtained spectra were red-shifted in the range of 30 nm to 40 nm and Gaussian broadenings of \u003cem\u003es\u003c/em\u003e = 0.2 eV or 0.3 eV were applied. Intensities of calculated ECD spectra were scaled to experimental ones. For ECD experiments where isomers with (\u003cem\u003eS\u003c/em\u003e)-configured stereocenter were measured, the resulting ECD spectra were mirrored for consistent representation of (\u003cem\u003eR\u003c/em\u003e)-configured isomeric behavior. a) UV/vis and ECD spectra of isomer \u003cstrong\u003eA-1\u003c/strong\u003e measured at –160 °C (the experimental ECD spectrum was mirrored). b) UV/vis and ECD spectra of isomer \u003cstrong\u003eB-1\u003c/strong\u003e measured at –160 °C (the experimental ECD spectrum was mirrored). c) UV/vis and ECD spectra of isomer \u003cstrong\u003eC-1\u003c/strong\u003e measured at –120\u0026nbsp;°C. d) UV/vis and ECD spectra of isomer \u003cstrong\u003eD-1\u003c/strong\u003e measured at –120 °C. e) Experimental UV/vis and ECD spectra recorded at –160 °C before irradiation of isomer \u003cstrong\u003eA-1\u003c/strong\u003e (green), after irradiation with 450 nm light leading to isomer \u003cstrong\u003eB-1\u003c/strong\u003e (pink), and after thermal annealing in the dark leading to isomer \u003cstrong\u003eC-1\u003c/strong\u003e (blue). ECD spectra were mirrored. f) Experimental UV/vis and ECD spectra recorded at –120 °C before irradiation of isomer \u003cstrong\u003eC-1\u003c/strong\u003e (blue), after irradiation with 450 nm light leading to isomer \u003cstrong\u003eD-1\u003c/strong\u003e (red), and after thermal annealing in the dark leading to isomer \u003cstrong\u003eA-1\u003c/strong\u003e (green).\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/bf3eb014817d574575f224f2.png"},{"id":51137709,"identity":"ac0b3f28-f649-4967-8a81-35bfa4256a2e","added_by":"auto","created_at":"2024-02-14 18:47:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1628858,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/4bf156b0-2b8d-4a6f-baa1-2c7e262afd8f.pdf"},{"id":51137059,"identity":"9c84361a-1b97-4019-bc64-25aa0e902cda","added_by":"auto","created_at":"2024-02-14 18:39:40","extension":"cif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1037180,"visible":true,"origin":"","legend":"Supplementary Data Set 1","description":"","filename":"22DubPB01RCCDC2307158.cif","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/9b1cdd62f5782ba9fc3cf15d.cif"},{"id":51137061,"identity":"15127a2b-e436-4ab3-9dfe-08c6122bfaef","added_by":"auto","created_at":"2024-02-14 18:39:40","extension":"cif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":582995,"visible":true,"origin":"","legend":"Supplementary Data Set 2","description":"","filename":"23DubAO01CCDC2307157.cif","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/ab9d9e5ed7fb434b0d2254ae.cif"},{"id":51137066,"identity":"01c13cee-53b7-412e-af1c-9d007600e2fe","added_by":"auto","created_at":"2024-02-14 18:39:41","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":5551748,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Information\u003c/p\u003e","description":"","filename":"BiswasOzcelikDubeSI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3660237/v1/51fa20adc2975b1914b290d0.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"A Supercharged Molecular Motor Operating by Constitutional Alteration and Hydrogen Bonding","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMolecular motors have gained considerable traction as nanoscale powering units for advanced molecular machines and nanotechnology.\u003csup\u003e1\u0026ndash;5\u003c/sup\u003e The central feature of molecular motors is their directional motions fueled by different sources of energy.\u003csup\u003e6\u003c/sup\u003e A variety of designs are available nowadays\u003csup\u003e7\u0026ndash;14\u003c/sup\u003e and light powered versions stand out because of the straight forward and waste free energy supply (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea).\u003csup\u003e15\u0026ndash;17\u003c/sup\u003e After Feringa and coworkers developed the first design of a working molecular motor in 1999,\u003csup\u003e18\u003c/sup\u003e different generations of the overcrowded alkene-based motors were brought forward by the same group. The difference between these generations lies in the number of stable stereogenic centers (two for generation I,\u003csup\u003e18\u003c/sup\u003e one for generation II,\u003csup\u003e19\u003c/sup\u003e and only a pseudo-chiral center in generation III\u003csup\u003e20\u003c/sup\u003e), which provide permanent asymmetry to the molecular structures. A source of permanent asymmetry is necessary to control directionality of the motors. The common working mechanism of Feringa-type motors is comprised of two photoisomerization steps, which are intersected by two ratcheting thermal helix inversion (THI) steps. A number of alternative designs for light driven molecular motors have been developed and experimentally proven since. In 2014 Greb and Lehn developed an imine-based molecular motor system, in which thermal ratcheting steps are imine-inversion or ring-flip processes instead of THI.\u003csup\u003e21, 22\u003c/sup\u003e Again, a carbon-based stereocenter bearing differently sized groups serves as source of asymmetry. In 2015 our group presented a hemithioindigo (HTI)-based molecular motor, which can be powered by visible light and works by a closely related mechanism to the Feringa motors.\u003csup\u003e23\u0026ndash;25\u003c/sup\u003e In 2018 we established the first photon-only molecular motor, which does not require thermal steps in its working mechanism but functions by three consecutive irradiation steps.\u003csup\u003e26\u003c/sup\u003e This different mechanism leads to unique properties, for example the motor becomes faster and more efficient with decreasing temperature. One year later we reported on yet a different type of molecular motor, which performs a directional figure of eight shaped motion instead of the hitherto possible circular motions.\u003csup\u003e27\u003c/sup\u003e The working mechanism of the latter involves thermal hula-twist isomerizations as ratcheting steps instead of THIs, i.e. the synchronized rotation of the central double bond and a directly adjacent single bond. Further designs have emerged since, including biomimetic artificial motors\u003csup\u003e28, 29\u003c/sup\u003e and a number of theoretically predicted versions.\u003csup\u003e30\u0026ndash;37\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn principle it is possible to imagine other sources of directionality control in light-driven molecular motors and weak interactions have been discussed for some time in this regard. In particular hydrogen bonding was identified in a theoretical study as early as 2013 by the groups of Sampedro and Frutos to be a very interesting candidate for controlling directionality.\u003csup\u003e38\u003c/sup\u003e Related endeavors have put forward supramolecular hydrogen bonding interactions to remote-control the directionality of the motor.\u003csup\u003e39, 40\u003c/sup\u003e Most recently a molecular motor with intramolecular hydrogen bonding was disclosed by Crespi and Feringa using a chiral hydroxy-indanone rotor and a barbituric acid stator part.\u003csup\u003e41\u003c/sup\u003e Here the source of asymmetry is the hydroxy-bearing stereocenter adjacent to the rotating central double bond, which forms a hydrogen bond to the stator carbonyl function. This places the intramolecular hydrogen bonding in an ideal position to influence the rotation process. The described working mechanism encompasses again four steps, two light induced double-bond isomerizations and two intersecting thermal helix inversions, similar to the working mechanism of the original Feringa motor.\u003c/p\u003e \u003cp\u003eIn this work we present a molecular motor setup \u003cb\u003e1\u003c/b\u003e employing a similar intramolecular hydrogen bonding interaction to control the light-powered unidirectional rotation process (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). However, different to all earlier described molecular motor mechanisms, we found that motor \u003cb\u003e1\u003c/b\u003e undergoes a five-step motion cycle involving a hitherto unprecedented constitutional alteration and subsequent hydrogen-bond directed rotation. In this process light induced double bond isomerization is tied to intramolecular epoxide formation and proton transfer producing a high-energy intermediate, which stores a substantial amount of the incident light energy. The conformation of the epoxide structure, and hence the rotary state of the motor, is held in place by intramolecular hydrogen bonding with inverted donor and acceptor, which fully determines the directionality of the rotation. A follow-up thermal step opens up the epoxide and restores the original constitution of the motor while quantitatively ratcheting the directional motion. For the remaining two steps in the motor mechanism the expected light induced double bond isomerization and thermal helix inversion are observed without constitutional alteration. This unique motor mechanism provides unprecedented opportunities, especially for harnessing much more energy of the incident light within the course of the directional rotation. Taken together our findings open the door to a fully unknown mechanistic realm for creating and controlling directional motions at the smallest scales. They thus provide unique opportunities for designing and applying light-driven molecular motors with strongly enhanced power for a next generation of molecular machines.\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eSo far, the source of asymmetry in all HTI-based molecular motors is a sulfoxide with point chirality instead of a carbon stereogenic center to control directionality.\u003csup\u003e23\u0026ndash;27, 42, 43\u003c/sup\u003e For HTI motor \u003cstrong\u003e1\u003c/strong\u003e, we have now changed the asymmetry source to a carbon based stereocenter, which resides on the indanone- in place of the thioindigo fragment. This stereogenic center invokes an alcohol moiety in close proximity to the central double bond \u0026ndash; the axis of directional rotation \u0026ndash; which can form an intramolecular hydrogen bond to the stator fragment. The sulfur atom at the thioindigo fragment is not oxidized, which is expected to lead to a notable red-shift of the absorption of the motor as compared to the related structural setup of first generation HTI-based motors. A bromide is introduced at the thioindigo fragment for the dual purpose of facilitating synthesis (as halogenated benzothiophenones are more stable and less prone to form thioindigo as side product) and to introduce a convenient handle for late-stage functionalization and applications.\u003c/p\u003e\n\u003cp\u003eA theoretical analysis on the DFT level of theory was conducted first to elucidate the motor rotation mechanism of \u003cstrong\u003e1\u003c/strong\u003e. A direct comparison was made to the behavior of ether-derivative \u003cstrong\u003e2\u003c/strong\u003e lacking hydrogen bonding capacity. For clarity only structures with (\u003cem\u003eR\u003c/em\u003e)-configured stereocenter are considered in the following. The theoretical description of \u003cstrong\u003e1\u003c/strong\u003e reveals a very unusual yet very well-suited energy surface for proper unidirectional light powered motor rotation (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The global minimum structure \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e possesses \u003cem\u003eE\u003c/em\u003e configuration of the central double bond and allows intramolecular hydrogen bonding between the hydroxy group and the carbonyl function of the thioindigo fragment. A (\u003cem\u003eP\u003c/em\u003e)-helicity is adopted in this structure, which brings the larger \u003cem\u003ei\u003c/em\u003e-propyl substituent at the stereogenic center to the same side as the methoxy-group in \u003cem\u003eortho\u003c/em\u003e-position with regard to the double bond. With the helicity already hinting at the rotation direction, photoisomerization in a counterclockwise manner would lead to population of isomer \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e with \u003cem\u003eZ\u003c/em\u003e configured double bond and (\u003cem\u003eM\u003c/em\u003e)-helicity. Now the hydroxy group at the stereocenter and the \u003cem\u003eortho\u003c/em\u003e-methoxy group are placed at the same side of the molecule. During this photoconversion intramolecular hydrogen bonding with the carbonyl is disrupted. In the calculation no significant hydrogen bonding interaction between the hydroxy group as donor and the sulfur atom as acceptor are found. A chalcogen bonding interaction between the sulfur and the carbonyl oxygen, as recently observed in heterocylic HTI photoswitches,\u003csup\u003e44\u003c/sup\u003e is also not likely in this case (see Supporting Information for details). Isomer \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e possesses a very high energy of 7.55 kcal/mol according to theory and stabilizes in a thermal step by inverting helicity. This helix inversion continues the directional rotation and serves as ratcheting step in the motor mechanism. A transition state with 9.6 kcal/mol elevated energy is predicted for this process. As a result, isomer \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e with \u003cem\u003eZ\u003c/em\u003e-configuration of the double bond and (\u003cem\u003eP\u003c/em\u003e)-helicity is formed. The energy of isomer \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e is predicted to be lowered by 4.43 kcal/mol as compared to \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, which leads to complete conversion at ambient to high temperatures. Still, the stabilized isomer \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e possesses a significantly higher energy than the global minimum by 3.7 kcal/mol. Taken together, these values belong to the highest amounts of photoenergy being stored in metastable HTI switches and motor systems so far. The significant energy content would lead to a complete thermal conversion from \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to isomer \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e at elevated temperatures. The sequence of isomer interconversions from \u003cstrong\u003eA\u003c/strong\u003e to \u003cstrong\u003eB\u003c/strong\u003e to \u003cstrong\u003eC\u003c/strong\u003e represents the first 180\u0026deg; unidirectional rotation of motor \u003cstrong\u003e1\u003c/strong\u003e. We expected a similar two-step interconversion between three isomers for the second 180\u0026deg; rotation instead of the population of an additionally and highly unusual epoxide-intermediate \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. Photoirradiation of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e would thus continue rotation in a counterclockwise sense leading to population of metastable isomer \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e with \u003cem\u003eE\u003c/em\u003e-configured double bond and (\u003cem\u003eM\u003c/em\u003e)-helicity. Intramolecular hydrogen bonding would be reestablished in this step with the carbonyl as acceptor. In \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e again the smaller hydroxy group at the stereocenter and the \u003cem\u003eortho\u003c/em\u003e-methoxy group are located on the same side of the molecule. Isomer \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e is calculated to be 2.3 kcal/mol higher in energy compared to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and could thus be converted completely into the latter by another thermal helix inversion step. However, we found in the calculations, that in this process intramolecular hydrogen bonding is retained and the predicted transition state is only 1.8 kcal/mol higher in energy. With such low transition state energy an experimental observation of the thermal \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e conversion would not be possible without resorting to ultrafast transient spectroscopy methods. In contradiction to this initial theoretical assessment, we found a conveniently stable intermediate experimentally, which decayed completely into \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e with an associated Gibbs energy of activation of 13.0 kcal/mol. Since also experimental spectroscopy evidences (see below) and theoretical spectra did not match for the expected isomer \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, we returned to a more comprehensive theoretical assessment. Two options were taken into account guided by the experimental observation that UV/vis absorption is strongly hypsochromically shifted. To explain this behavior we assumed that conjugation via the central double bond is broken in the experimentally observed intermediate and either an epoxide or a furane-based structure is formed. As is described in more detail in the Supporting Information, the calculated epoxide structure \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e matches very well both energetically and spectroscopically with the experimentally observed intermediate. \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e is formed by a conjugated intramolecular epoxidation reaction while at the same time the hydrogen bond donor shifts to the former carbonyl \u0026ndash; and now enol - site of the thioindigo fragment. A strong intramolecular hydrogen bond is formed between the enol and the epoxide, locking the structure in a nearly perpendicular arrangement of the indanone rotor versus the thioindigo stator. \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e thus represents a \u0026ldquo;trapped\u0026rdquo; 90\u0026deg; rotation intermediate possessing an exceptional high energy of 12 kcal/mol. This large portion of energy is directly stored from the incident light irradiation and could thus be expended to do actual work in the thermally activated follow up steps. It establishes an unprecedented supercharging of a light-driven molecular motor. The next thermally activated step is calculated to be an epoxide opening and proton transfer step, which is tied to further rotation to reach intermediate \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. The initial rotation direction is maintained in this step and a considerable Gibbs energy of activation of 14.9 kcal/mol is predicted. The final \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e thermal helix inversion step was found in the initial calculations as described above. With the theoretically predicted energy profile a quantitative directionality is expected for motor \u003cstrong\u003e1\u003c/strong\u003e even at higher temperatures. Low temperature experiments should allow to observe four different isomers \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, and \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and thus evidence unidirectionality directly.\u003c/p\u003e\n\u003cp\u003eTo complete the theoretical analysis NMR, UV/vis as well as ECD spectra were calculated at the CAM-B3LYP/6-311G(d,p) level of theory and the effect of different solvents (THF or Et\u003csub\u003e2\u003c/sub\u003eO) were included through the polarizable continuum model (PCM) (see Supporting Information for details). The hydroxy group proton signal in the \u003csup\u003e1\u003c/sup\u003eH NMR spectrum was found to be especially sensitive to the particular isomeric state and thus was predicted to be a powerful probe for conformational analysis. UV/vis spectra report on significant electronic changes such as \u003cem\u003eE\u003c/em\u003e or \u003cem\u003eZ\u003c/em\u003e configuration of the central double bond and especially its braking during the constitutional alteration step. Electronic circular dichroism (ECD) spectra are highly sensitive to the particular helicity of the isomers, which would complete an unambiguous assignment of spectral species in the experiments.\u003c/p\u003e\n\u003cp\u003eA similar theoretical analysis was conducted for methoxy-substituted derivative \u003cstrong\u003e2\u003c/strong\u003e lacking the capacity for intramolecular hydrogen bonding. In this case the energy profile reveals that compound \u003cstrong\u003e2\u003c/strong\u003e also is a motor but adheres to the classical four-step cycle (including states \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e, \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e, \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e, and \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e) with alternating photochemical and thermal helix inversion steps. The sense of directionality is the same as in motor \u003cstrong\u003e1\u003c/strong\u003e, which directly shows that hydrogen bonding in this classical rotation mechanism is not responsible for unidirectionality. Additionally, the \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e isomer is now the global minimum and significantly less energy is stored in the metastable states \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e (3.13 kcal/mol) and \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e (4.84 kcal/mol). With this energy profile full unidirectionality would still be present, as the thermal helix inversion steps from \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e to \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e and \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e still lead to complete conversions and thus to effective ratcheting. Like for \u003cstrong\u003e1\u003c/strong\u003e the most stable structures \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e and \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e feature a \u003cem\u003esyn\u003c/em\u003e-relation of the large \u003cem\u003ei\u003c/em\u003e-propyl group and the aromatic methoxy group in \u003cem\u003eortho\u003c/em\u003e-position to the central double bond at the five membered indanone ring. It thus becomes clear that the size differences at the stereogenic center are primarily responsible for dictating the sense of directionality.\u003c/p\u003e\n\u003cp\u003eSynthesis of motor \u003cstrong\u003e1\u003c/strong\u003e is described in detail in the Supporting Information and starts from commercially available 3-(2,5-dimethoxyphenyl)propanoic acid (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). After intramolecular Friedel-Crafts acylation the corresponding 4,7-dimethoxy-indanone (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e) is obtained to which the \u003cem\u003ei\u003c/em\u003e-propyl group was introduced via alpha-deprotonation and substitution with \u003cem\u003ei\u003c/em\u003e-propyl iodide. The resulting indanone \u003cstrong\u003e5\u003c/strong\u003e was obtained in 31% yield. To our surprise prolonged treatment of \u003cstrong\u003e5\u003c/strong\u003e with base led to formation of the alpha-hydroxylated indanone \u003cstrong\u003e6\u003c/strong\u003e. A similar reaction has been reported just when writing this manuscript by Crespi, Feringa, and co-workers under Lewis-acid conditions,\u003csup\u003e41\u003c/sup\u003e which we were not aware of at the time when synthesizing our motor. After optimization a satisfactory yield of 60% was achieved when bubbling air through the solution to increase the dioxygen reactant level. A future closer examination of this reaction will reveal details about the mechanism and probe its scope, however it is already evident that the hydroxy group stems from the air\u0026rsquo;s dioxygen. Condensation of indanone \u003cstrong\u003e6\u003c/strong\u003e and benzothiophenone \u003cstrong\u003e7\u003c/strong\u003e in the presence of BCl\u003csub\u003e3\u003c/sub\u003e gave the final motor \u003cstrong\u003e1\u003c/strong\u003e in 23% yield. Single crystals suitable for X-ray analysis could be obtained for the two stable isomers, the global minimum \u003cem\u003eE\u003c/em\u003e-isomeric \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e as well as for metastable \u003cem\u003eZ\u003c/em\u003e-isomeric \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, directly evidencing the molecular structure and intramolecular hydrogen bonding in \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). Deuteration experiments allowed to identify the \u003csup\u003e1\u003c/sup\u003eH NMR signals of the OH proton in the different isomers of motor \u003cstrong\u003e1\u003c/strong\u003e directly (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e\n\u003cp\u003eAfter successful synthesis the thermal behavior of motor \u003cstrong\u003e1\u003c/strong\u003e was scrutinized first. At ambient temperature only two isomers could be observed and fully characterized, \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, as predicted by theory. The metastable isomer \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e was isolated after irradiation of \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e with 450 nm light and flash column chromatography separation of the two isomers. Upon prolonged heating to 50\u0026deg;C in CDCl\u003csub\u003e3\u003c/sub\u003e solution \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e is completely converted into \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. When conservatively assuming that remaining 5% of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e cannot be observed in the \u003csup\u003e1\u003c/sup\u003eH NMR experiment, the resulting equilibrium constant \u003cem\u003eK\u003c/em\u003e\u0026thinsp;=\u0026thinsp;95/5 at 50\u0026deg;C can then be translated into the corresponding Gibbs energy difference between \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e \u0026Delta;\u003cem\u003eG\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.9 kcal/mol. This value is the lower limit of the energy difference between the two isomers and thus the theoretically predicted value of 4.86 kcal/mol difference is supported by experiment. A corresponding Gibbs energy of activation of \u0026Delta;\u003cem\u003eG\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026Dagger;\u003c/em\u003e\u003c/sup\u003e = 25 kcal/mol was determined from kinetic analysis of the thermal \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e conversion.\u003c/p\u003e\n\u003cp\u003eNext irradiation experiments were conducted at low temperatures to evidence the direct photoproducts formed upon irradiation of \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. Starting from \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, \u003cem\u003ein situ\u003c/em\u003e irradiation at \u0026minus;\u0026thinsp;130\u0026deg;C in a 1:1 mixture of THF-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e8\u003c/sub\u003e : CS\u003csub\u003e2\u003c/sub\u003e revealed the formation of one new isomer as the direct photoproduct first and subsequently formation of isomer \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e as well (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec). The isomer populated first could not be accumulated strongly even at the low temperature but quickly reached a steady state concentration while the population of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e further increased upon continued irradiation. When switching off the light and raising the temperature slightly to \u0026minus;\u0026thinsp;125\u0026deg;C, the first formed isomer thermally converted exclusively into \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ed). The kinetic analysis delivered a Gibbs energy of activation of \u0026Delta;\u003cem\u003eG\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026Dagger;\u003c/em\u003e\u003c/sup\u003e = 9.67 kcal/mol for this process (see Supporting Information for details). This behavior is fully consistent with the predicted properties of isomer \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, which could thus be assigned as the direct photoproduct of \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. A complementary set of experiments was conducted to investigate the photoisomerization of isomer \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. To our surprise irradiation of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e at \u0026minus;\u0026thinsp;105\u0026deg;C in THF-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e8\u003c/sub\u003e solution resulted in the population of a fourth isomer, which could be accumulated almost quantitatively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ee). This strong accumulation allowed a thorough \u003csup\u003e1\u003c/sup\u003eH NMR analysis at low temperatures (\u0026ndash;108\u0026deg;C to \u0026minus;\u0026thinsp;120\u0026deg;C) including NOE experiments to evidence the \u003cem\u003eE\u003c/em\u003e configuration of the (supposed to be intact) double bond (see Supporting Information for all details of this analysis). However, upon closer scrutiny, 2D NMR analysis revealed that no carbonyl-carbon signal could be detected. Further, signal shifts of the expected central double bond-carbon atoms as well as the stereogenic carbon center also did not match with their expected hybridization or substitution-character. Thermal annealing of the new isomer at \u0026minus;\u0026thinsp;80\u0026deg;C in the dark led to full conversion to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ef). The corresponding kinetic analysis revealed a Gibbs energy of activation of \u0026Delta;\u003cem\u003eG\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026Dagger;\u003c/em\u003e\u003c/sup\u003e = 13 kcal/mol for this process, which is in stark contrast to the expected barrier for thermal \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e conversion. Because of these accumulated experimental evidences and discrepancy to the calculations it became clear that this fourth isomer could not be \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. However, remarkably good agreement between theoretically calculated and experimental NMR spectra were found for the epoxide constitutional isomer \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (see below). Moreover, also the calculated Gibbs energy of activation for thermal \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e conversion matches very well with the experimentally established value for the intermediate decay.\u003c/p\u003e\n\u003cp\u003eIn order to fully support the tentative isomer assignment of the intermediate to \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e as well as assignments of the other isomers, theoretically predicted NMR, UV/vis, and ECD spectra were compared to experimental ones (see Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e and the Supporting Information for more details). The theoretically predicted \u003csup\u003e1\u003c/sup\u003eH NMR chemical shifts are in very good agreement with the experiments under the assumption that the photoproduct of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e irradiation is indeed \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (see Supporting Information for the detailed comparison of experimental and theoretical \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e spectra). UV/vis spectra and ECD spectra of \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, and \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e could be directly compared between low temperature experiment and theory and again a very good agreement was found (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea-d). To this end EPA (5:5:2 mixture of Et\u003csub\u003e2\u003c/sub\u003eO: \u003cem\u003ei\u003c/em\u003e-pentane: EtOH) was used as solvent to access very low temperatures, which allowed to obtain the UV/vis and ECD spectra for the pure \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e isomer at \u0026minus;\u0026thinsp;120\u0026deg;C and even the full spectral signature of the fleeting \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e isomer at \u0026minus;\u0026thinsp;160\u0026deg;C. When irradiating enantiomerically pure \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e at \u0026minus;\u0026thinsp;160\u0026deg;C the UV/vis spectrum displayed a bathochromic shift, while the ECD spectrum changed signs of the Cotton effect (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ee). This behavior reveals first, that the conjugation of the central double bond is not broken in the intermediate and second, that it possesses opposite helicity. Further the bathochromic absorption shift is indicative for a change from \u003cem\u003eE\u003c/em\u003e to \u003cem\u003eZ\u003c/em\u003e configuration of the central double bond similar to HTI photoswitches in general (note that in HTIs the \u003cem\u003eE\u003c/em\u003e and \u003cem\u003eZ\u003c/em\u003e nomenclature appears inverted because of the particular substitution pattern and resulting CIP priorities of \u003cstrong\u003e1\u003c/strong\u003e). A very good match with the calculated UV/vis and ECD spectra of \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e is observed in this case, which thus could confidently be assigned (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb). Thermal annealing at \u0026minus;\u0026thinsp;108\u0026deg;C led to the known spectra of \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ee) directly reporting on full unidirectionality for the whole \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eB\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e conversion sequence. When irradiating enantiomerically pure \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e at \u0026minus;\u0026thinsp;120\u0026deg;C a very distinct behavior was observed (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ef). A new intermediate state formed with strongly hypsochromically shifted absorption. In fact, no absorption in the visible range remained after full conversion in the pss, which directly evidences breaking of the central double bond and thus loss of conjugation in the intermediate isomer. Besides the UV/vis absorption also the corresponding ECD spectrum could very well be matched with the theoretically predicted one of intermediate \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ed), which allowed us to now unambiguously assign this isomer. It was thus found that a highly unusual constitutional alteration takes place in the photochemical \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e transition, which retains a large amount of the incident lights energy according to the theoretical description. Thermal annealing at \u0026minus;\u0026thinsp;80\u0026deg;C led to full conversion to the \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e isomer as evidenced by both UV/vis and ECD spectral changes without the observable formation of state \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ef). This behavior is expected from the very small calculated Gibbs energy of activation for the THI, which leads from \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. Therefore, \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e seems to directly convert to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e at the temperature of the experiment but does in fact undergo first epoxide ring opening to \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and then quick follow-up THI to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, which cannot be evidenced individually by experiment.\u003c/p\u003e\n\u003cp\u003eOverall, the combined NMR, UV/vis and ECD experiments allowed an unambiguous isomer assignment confirming constitutional alteration as a key-step as well as complete unidirectionality of motor \u003cstrong\u003e1\u003c/strong\u003e. Especially noteworthy is the completely selective conversion of \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and then to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, since isomer \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e inherits a single bond instead of the configurationally stable double bond as rotation axis. It is only because of the significant intramolecular hydrogen bond that the rotation direction is not reversed in the thermal follow up step, which would populate \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e instead \u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e. Our calculations show that \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e is the global minimum of the epoxide state, which is not the case when the OH proton is replaced by a methyl group \u003cem\u003ein silico\u003c/em\u003e (see Supporting Information for the corresponding data). The hydrogen bonding effect is present even in protic solvents like MeOD-\u003cem\u003ed\u003c/em\u003e\u003csub\u003e4\u003c/sub\u003e (see below and the Supporting Information) and despite an apparent proton-deuterium exchange. Thus, intramolecular hydrogen bonding is truly dictating the sense of directionality in the \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e rotation sequence and thus is responsible for motion control instead of sterics. Interestingly this is not the case for the \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eB-1\u003c/strong\u003e to \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e rotation sequence, although intramolecular hydrogen bonding is present in isomer \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and needs to be broken in the photochemical step. However, we found that when the OH proton is replaced again by a methyl group \u003cem\u003ein silico\u003c/em\u003e, the inherent directionality of the corresponding \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e to \u003cstrong\u003eB-2\u003c/strong\u003e to \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e2\u003c/strong\u003e rotation sequence is retained and thus is the same as in motor \u003cstrong\u003e1\u003c/strong\u003e. It becomes apparent that isomers \u003cstrong\u003eA\u003c/strong\u003e are more stable than isomers \u003cstrong\u003eB\u003c/strong\u003e within this molecular setup in general, which is a steric effect that favors the \u003cem\u003ei\u003c/em\u003e-propyl group residing at the same side of the indanone plane as the phenyl-methoxy (see the Supporting Information for more details).\u003c/p\u003e\n\u003cp\u003eWhen comparing the kinetics for the thermal helix inversion from \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e (both intramolecularly hydrogen bonded) no strong influence of the solvent polarity was observed. Kinetic analysis in MeOH or THF delivered roughly the same Gibbs energy of activation of \u0026Delta;\u003cem\u003eG\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026Dagger;\u003c/em\u003e\u003c/sup\u003e = 13 kcal/mol for this process (see Supporting Information). It has to be emphasized however, that for this process no full disruption of the intramolecular hydrogen bond is needed for the conversion from \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e to \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e but rather a proton hopping during re-tautomerization and epoxide opening. Therefore, possible effects of the solvent are likely to cancel out rather than preferring one isomeric state and significantly altering the energy landscape.\u003c/p\u003e\n\u003cp\u003eIt finally needs to be emphasized that a significant red shift of about 50 nm is seen for the absorptions of the stable \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e and \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e isomers when compared to the structurally related first HTI motor inheriting a sulfoxide as stereogenic center. Such red shift of absorption is desirable for many applications of molecular motors e.g. in the context of biology, catalysis, or materials and thus makes motor \u003cstrong\u003e1\u003c/strong\u003e a highly interesting candidate in this regard.\u003c/p\u003e\n\u003cp\u003eIn conclusion, we describe a HTI-based light driven molecular motor \u003cstrong\u003e1\u003c/strong\u003e inheriting intramolecular hydrogen bonding. Different to all earlier HTI-motor setups, motor \u003cstrong\u003e1\u003c/strong\u003e receives its asymmetry from a carbon-based stereogenic center located at the indanone fragment. We demonstrate that this asymmetry is effectively translated into complete unidirectionality of the motor rotation. We further evidence that hydrogen bonding is in fact responsible for unidirectionality of this motor. A unique and distinct operation mechanism is established in which constitutional alteration and tautomerization processes allow to store an unprecedented large amount of the provided light energy within the motor rotation cycle. With this molecular setup a new type of molecular motors has become available that can be supercharged by light irradiation. This progress will open up an unexplored realm of motor applications where a significant energy budget or workload is expended e.g. in active mechanically driven processes\u003csup\u003e45\u0026ndash;50\u003c/sup\u003e or bulk material changes.\u003csup\u003e51\u0026ndash;55\u003c/sup\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH. Dube thanks the Deutsche Forschungsgemeinschaft (DFG) for an Emmy Noether fellowship (DU 1414/1-2). A. Ozcelik thanks the Alexander von Humboldt Foundation for a postdoctoral fellowship. We further thank C. Placht for considerable help with NMR measurements at variable temperatures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.D., P.K.B. and A.O. conceived and designed the project. P.K.B. synthesized and characterized all compounds, crystallized \u003cstrong\u003eC\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e for X-ray analysis, and conducted the initial thermal and photochemical measurements as well as data analysis. A.O. purified and isolated different isomers, crystallized \u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e for X-ray analysis, characterized \u003cstrong\u003eD\u003c/strong\u003e-\u003cstrong\u003e1\u003c/strong\u003e, conducted the in depth thermal and photochemical measurements as well as data analyses, and provided the initial quantum chemical description. M.H. provided the in-depth quantum chemical characterization of the motor. H.D. wrote the paper and edited the Supplementary Information. All contributors discussed, edited, and refined the work and the written manuscript and Supplementary Information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCostil, R.; Holzheimer, M.; Crespi, S.; Simeth, N. A.; Feringa, B. L., Directing Coupled Motion with Light: A Key Step Toward Machine-Like Function. \u003cem\u003eChem. Rev. \u003c/em\u003e\u003cstrong\u003e2021,\u003c/strong\u003e \u003cem\u003e121\u003c/em\u003e (21), 13213-13237.\u003c/li\u003e\n\u003cli\u003eKrause, S.; Feringa, B. L., Towards artificial molecular factories from framework-embedded molecular machines. \u003cem\u003eNat. Rev. 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P.; Giuseppone, N., Dual-light control of nanomachines that integrate motor and modulator subunits. \u003cem\u003eNat. Nanotechnol. \u003c/em\u003e\u003cstrong\u003e2017,\u003c/strong\u003e \u003cem\u003e12\u003c/em\u003e, 540-545.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3660237/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3660237/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMolecular rotary motors undergo directional motions upon input of external energy and represent archetypical molecular machines. Light driven variants stand out as particularly easy to fuel continuously and potentially carrying a very high energy content during their action. So far, such motors function via light induced bond rotations where the directionality is dictated by a fixed source of asymmetry within the structure. During the operation cycle there is no further structural change happening except for the rotation itself. In this work we disclose a hitherto unknown and highly effective mechanism for light driven motor rotation, which makes use of constitutional alteration of the structure. This in turn allows the directionality to be controlled actively by an intramolecular hydrogen bond instead of sterics. Associated with this unusual mechanism is a particularly high energy content that the motor retains from the incident light, which is of great importance for application of molecular motors working under external load. With these findings unique possibilities emerge for the design and use of molecular motors with unprecedented modes of action and power.\u003c/p\u003e","manuscriptTitle":"A Supercharged Molecular Motor Operating by Constitutional Alteration and Hydrogen Bonding","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-14 18:39:35","doi":"10.21203/rs.3.rs-3660237/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-chemistry","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nchem","sideBox":"Learn more about [Nature Chemistry](http://www.nature.com/nchem/)","snPcode":"","submissionUrl":"","title":"Nature Chemistry","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0bc04d0c-deae-430c-8c91-cffd73740b23","owner":[],"postedDate":"February 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":28733369,"name":"Physical sciences/Chemistry/Organic chemistry"},{"id":28733370,"name":"Physical sciences/Chemistry/Photochemistry"},{"id":28733371,"name":"Physical sciences/Nanoscience and technology/Nanoscale devices/Molecular machines and motors"}],"tags":[],"updatedAt":"2026-03-27T16:40:55+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-14 18:39:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3660237","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3660237","identity":"rs-3660237","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}