Intrinsically unidirectional chemically fuelled rotary molecular motors.

Biological systems mainly utilize chemical energy to fuel autonomous molecular motors, enabling the system to be driven out of equilibrium1. Taking inspiration from rotary motors such as the bacterial flagellar motor2 and adenosine triphosphate synthase3, and building on the success of light-powered unidirectional rotary molecular motors4-6, scientists have pursued the design of synthetic molecular motors solely driven by chemical energy7-13. However, designing artificial rotary molecular motors operating autonomously using a chemical fuel and simultaneously featuring the intrinsic structural design elements to allow full 360° unidirectional rotary motion like adenosine triphosphate synthase remains challenging. Here we show that a homochiral biaryl Motor-3, with three distinct stereochemical elements, is a rotary motor that undergoes repetitive and unidirectional 360° rotation of the two aryl groups around a single-bond axle driven by a chemical fuel. It undergoes sequential ester cyclization, helix inversion and ring opening, and up to 99% unidirectionality is realized over the autonomous rotary cycle. The molecular rotary motor can be operated in two modes: synchronized motion with pulses of a chemical fuel and acid-base oscillations; and autonomous motion in the presence of a chemical fuel under slightly basic aqueous conditions. This rotary motor design with intrinsic control over the direction of rotation, simple chemical fuelling for autonomous motion and near-perfect unidirectionality illustrates the potential for future generations of multicomponent machines to perform mechanical functions.

Synthetic molecular motor activates drug delivery from polymersomes.

The design of stimuli-responsive systems in nanomedicine arises from the challenges associated with the unsolved needs of current molecular drug delivery. Here, we present a delivery system with high spatiotemporal control and tunable release profiles. The design is based on the combination of an hydrophobic synthetic molecular rotary motor and a PDMS-b-PMOXA diblock copolymer to create a responsive self-assembled system. The successful incorporation and selective activation by low-power visible light (λ = 430 nm, 6.9 mW) allowed to trigger the delivery of a fluorescent dye with high efficiencies (up to 75%). Moreover, we proved the ability to turn on and off the responsive behavior on demand over sequential cycles. Low concentrations of photoresponsive units (down to 1 mol% of molecular motor) are shown to effectively promote release. Our system was also tested under relevant physiological conditions using a lung cancer cell line and the encapsulation of an Food and Drug Administration (FDA)-approved drug. Similar levels of cell viability are observed compared to the free given drug showing the potential of our platform to deliver functional drugs on request with high efficiency. This work provides an important step for the application of synthetic molecular machines in the next generation of smart delivery systems.

Mix and Match Tuning of the Conformational and Multistate Redox Switching Properties of an Overcrowded Alkene.

Overcrowded alkenes have received considerable attention as versatile structural motifs in a range of optical switches and light-driven unidirectional motors. In contrast, their actuation by electrochemical stimuli remains underexplored, even though this alternative energy input may be preferred in various applications and enables additional control over molecular switching states and properties. While symmetric bistricyclic overcrowded enes (BAEs) containing two identical halves based on either thioxanthene (TX) or acridine (Acr) motifs are known to be reversible conformational redox switches, their redox potentials are generally too high or low, respectively, thereby preventing wider applications. Herein, we demonstrate that the "mixed" TX-Acr switch possesses redox properties that lie between those of its parent symmetric analogs, enabling interconversion between three stable redox and conformational states at mild potentials. This includes the neutral anti-folded, the dicationic orthogonal, and a unique twisted monoradical cation state, the latter of which is only accessible in the case of the mixed TX-Acr switch and in a pathway-dependent manner. Consequently, with this multistate redox switch, a myriad of molecular properties, including geometry, polarity, absorbance, and fluorescence, can be modulated with high fidelity and reversibility between three distinct stable states. More generally, this study highlights the versatility of the "mix and match" approach in rationally designing redox switches with specific (redox) properties, which in turn is expected to enable a myriad of applications ranging from molecular logic and memory to actuators and energy storage systems.

Redox-Switchable Aromaticity in a Helically Extended Indeno[2,1-c]fluorene.

Molecular switches have received major attention to enable the reversible modulation of various molecular properties and have been extensively used as trigger elements in diverse fields, including molecular machines, responsive materials, and photopharmacology. Antiaromaticity is a fascinating property that has attracted not only significant fundamental interest but is also increasingly relevant in different applications, in particular organic (opto)electronics. However, designing systems in which (anti)aromaticity can be judiciously and reversibly switched ON and OFF remains challenging. Herein, we report a helicene featuring an indenofluorene-bridged bisthioxanthylidene as a novel switch wherein a simultaneous two-electron (electro)chemical redox process allows highly reversible modulation of its (anti)aromatic character. Specifically, the two thioxanthylidene rotors, attached to the initially aromatic indenofluorene scaffold via overcrowded alkenes, adopt an anti-folded structure, which upon oxidation convert to singly bonded, twisted conformations. This is not only associated with significant (chir)optical changes but importantly also results in formation of the fully conjugated, formally antiaromatic as-indacene motif in the helical core of the switch. This process proceeds without the buildup of radical cation intermediates and thus enables highly reversible switching of molecular geometry, aromaticity, absorbance, and chiral expression under ambient conditions, as evidenced by NMR, UV-vis, CD, and (spectro)electrochemical analyses, supported by DFT calculations. We expect this concept to be extendable to a wide range of robust antiaromatic-aromatic switches and to provide a basis for modulation of the structure and properties of these fascinating inherently chiral polycyclic π-scaffolds.

Coupled Rotary Motion in Molecular Motors.

Biological molecular machines play a pivotal role in sustaining life by producing a controlled and directional motion. Artificial molecular machines aim to mimic this motion, to exploit and tune the nanoscale produced motion to power dynamic molecular systems. The precise control, transfer, and amplification of the molecular-level motion is crucial to harness the potential of synthetic molecular motors. It is intriguing to establish how directional motor rotation can be utilized to drive secondary motions in other subunits of a multicomponent molecular machine. The challenge to design sophisticated synthetic machines involving multiple motorized elements presents fascinating opportunities for achieving unprecedented functions, but these remain almost unexplored due to their extremely intricate behavior. Here we show intrinsic coupled rotary motion in light-driven overcrowded-alkene based molecular motors. Thus far, molecular motors with two rotors have been understood to undergo independent rotation of each subunit. The new bridged-isoindigo motor design revealed an additional dimension to the motor's unidirectional operation mechanism where communication between the rotors occurs. An unprecedented double metastable state intermediate bridges the rotation cycles of the two rotor subunits. Our findings demonstrate how neighboring motorized subunits can affect each other and thereby drastically change the motor's functioning. Controlling the embedded entanglement of active intramolecular components sets the stage for more advanced artificial molecular machines.

Excited State Dynamics in Unidirectional Photochemical Molecular Motors.

Unidirectional photochemically driven molecular motors (PMMs) convert the energy of absorbed light into continuous rotational motion. As such they are key components in the design of molecular machines. The prototypical and most widely employed class of PMMs is the overcrowded alkenes, where rotational motion is driven by successive photoisomerization and thermal helix inversion steps. The efficiency of such PMMs depends upon the speed of rotation, determined by the rate of ground state thermal helix inversion, and the quantum yield of photoisomerization, which is dependent on the excited state energy landscape. The former has been optimized by synthetic modification across three generations of overcrowded alkene PMMs. These improvements have often been at the expense of photoisomerization yield, where there remains room for improvement. In this perspective we review the application of ultrafast spectroscopy to characterize the excited state dynamics in PMMs. These measurements lead to a general mechanism for all generations of PMMs, involving subpicosecond decay of a Franck-Condon excited state to populate a dark excited state which decays within picoseconds via conical intersections with the electronic ground state. The model is discussed in the context of excited state dynamics calculations. Studies of PMM photochemical dynamics as a function of solvent suggest exploitation of intramolecular charge transfer and solvent polarity as a route to controlling photoisomerization yield. A test of these ideas for a first generation motor reveals a high degree of solvent control over isomerization yield. These results suggest a pathway to fine control over the performance of future PMMs.

Molecular Motors' Magic Methyl and Its Pivotal Influence on Rotation.

Molecular motors have found a wide range of applications, powering a transition from molecules to dynamic molecular systems for which their motion must be precisely tuned. To achieve this adjustment, strategies involving laborious changes in their design are often used. Herein, we show that control over a single methyl group allows a drastic change in rotational properties. In this regard, we present the straightforward asymmetric synthesis of ß-methylated first-generation overcrowded-alkene-based molecular motors. Both enantiomers of the new motors were prepared in good yields and high enantiopurities, and these motors were thoroughly studied by variable-temperature nuclear magnetic resonance (VT-NMR), ultraviolet-visible (UV-vis), and circular dichroism (CD) spectroscopy, showing a crucial influence of the methylation pattern on the rotational behavior of the motors. Starting from a common chiral precursor, we demonstrate that subsequent methylation can drastically reduce the speed of the motor and reverse the direction of the rotation. We show for the first time that complete unidirectionality can be achieved even when the energy difference between the stable and metastable states is small, resulting in the coexistence of both states under ambient conditions without hampering the energy ratcheting process. This discovery opens the way for the design of more advanced first-generation motors.

Photoresponsive Biomimetic Functions by Light-Driven Molecular Motors in Three Dimensionally Printed Liquid Crystal Elastomers.

Despite the fascinating developments in design and synthesis of artificial molecular machines operating at the nanoscales, translating molecular motion along multiple length scales and inducing mechanical motion of a three-dimensional macroscopic entity remains an important challenge. The key to addressing this amplification of motion relies on the effective organization of molecular machines in a well-defined environment. By taking advantage of long-range orientational order and hierarchical structures of liquid crystals and unidirectional rotation of light-driven molecular motors, we report here photoresponsive biomimetic functions of liquid crystal elastomers (LCEs) by the repetitive unidirectional rotation of molecular motors using 3D printing. Molecular motors were built in the main chain of liquid crystals oligomers to serve as photoactuators. The oligomers were then used as the ink, and liquid crystal elastomers with different morphologies were printed. The obtained LCEs are able to conduct multiple types of motions including bending, helical coiling, closing of petals, and flipping of wings of a butterfly upon UV illumination, which paves the way for future design of responsive materials with enhanced complex actuating functions.

Photocontrol of the ß-Hairpin Polypeptide Structure through an Optimized Azobenzene-Based Amino Acid Analogue.

A family of neurodegenerative diseases, including Huntington's disease (HD) and spinocerebellar ataxias, are associated with an abnormal polyglutamine (polyQ) expansion in mutant proteins that become prone to form amyloid-like aggregates. Prior studies have suggested a key role for ß-hairpin formation as a driver of nucleation and aggregation, but direct experimental studies have been challenging. Toward such research, we set out to enable spatiotemporal control over ß-hairpin formation by the introduction of a photosensitive ß-turn mimic in the polypeptide backbone, consisting of a newly designed azobenzene derivative. The reported derivative overcomes the limitations of prior approaches associated with poor photochemical properties and imperfect structural compatibility with the desired ß-turn structure. A new azobenzene-based ß-turn mimic was designed, synthesized, and found to display improved photochemical properties, both prior and after incorporation into the backbone of a polyQ polypeptide. The two isomers of the azobenzene-polyQ peptide showed different aggregate structures of the polyQ peptide fibrils, as demonstrated by electron microscopy and solid-state NMR (ssNMR). Notably, only peptides in which the ß-turn structure was stabilized (azobenzene in the cis configuration) closely reproduced the spectral fingerprints of toxic, ß-hairpin-containing fibrils formed by mutant huntingtin protein fragments implicated in HD. These approaches and findings will enable better deciphering of the roles of ß-hairpin structures in protein aggregation processes in HD and other amyloid-related neurodegenerative diseases.

Introduction of Molecular Complexity via the Cross-Coupling of Lithium 1,4-Dioxene with Aryl Bromides.

The synthetic potential of substituted 1,4-dioxenes is well recognised, although the chemistry of 2-aryl-1,4-dioxenes is relatively unexplored. Their transition metal-catalysed synthesis has been limited to Stille-type cross-coupling chemistry, typically showing long reaction times, or proceeding at high reaction temperatures. Here we present a facile and general methodology for the cross-coupling of aryl bromides with lithium 1,4-dioxene, affording a range of 2-aryl-1,4-dioxenes in generally good yields. We highlight the synthetic applicability of this transformation at multigram scale, and demonstrate the versatility of the products by conversion of the dioxene units to various carbonyl-based functionalities. Additionally, we present a concise two-step synthesis of an arylated analogue to a known 1,4-dioxene-based antifungal agent.

Synthesis of Styrylbenzazole Photoswitches and Evaluation of their Photochemical Properties.

Styrylbenzazoles form a promising yet under-represented class of photoswitches that can perform a light-driven E-Z isomerization of the central alkene double bond without undergoing irreversible photocyclization, typical of the parent stilbene. In this work, we report the synthesis and photochemical study of 23 styrylbenzazole photoswitches. Their thermal stabilities, quantum yields, maximum absorption wavelengths and photostationary state (PSS) distributions can be tuned by changing the benzazole heterocycle and the substitution pattern on the aryl ring. In particular, we found that push-pull systems show large redshifts of the maximum absorption wavelengths and the highest quantum yields, whereas ortho-substituted styrylbenzazole photoswitches exhibit the most favorable PSS ratios. Taking advantage of both design principles, we produced 2,6-dimethyl-4-(dimethylamino)-styrylbenzothiazole, a thermally stable and efficient P-type photoswitch which displays negative photochromism upon irradiation with visible light up to 470 nm to obtain a near-quantitative isomerization with a very high quantum yield of 59 %. Furthermore, 4-hydroxystyrylbenzoxazole was demonstrated to be a pH-sensitive switch which exhibits a 100 nm redshift upon deprotonation. Ortho-methylation of its benzothiazole analogue improved the obtained PSS ratio in its deprotonated state from E : Z=53 : 47 to E : Z=18 : 82. We anticipate that this relatively unexplored class of photoswitches will form a valuable expansion of the current family of photoswitches.

Push-Pull Bis-Norbornadienes for Solar Thermal Energy Storage.

The norbornadiene/quadricyclane (NBD/QC) photoswitch pair represents a promising system for application in molecular solar thermal energy storage (MOST). Often, the NBD derivatives have very limited overlap with the solar spectrum, and substitution to redshift the absorption leads to a decrease in the gravimetric energy density. Dimeric systems mitigate this factor because two switches can 'share' a substituent. Here, we present five new NBD dimers with red-shifted absorption spectra. One dimer features the most red-shifted absorption onset (539 nm) and a significantly red-shifted absorption maximum (404 nm) for NBD systems reported so far, without compromising thermal half-life. Promising properties for high-performance MOST applications are demonstrated, such as high absorption onsets reaching 539 nm, and energy densities of 379 kJ/kg, while still maintaining long half-lives of the metastable isomer, up to 23 hours at 25 °C.

Push-Pull Bis-Norbornadienes for Solar Thermal Energy Storage.

Invited for the cover of this issue are Ben L. Feringa and co-workers at the University of Groningen. The image depicts an autumn forest with the five molecular switches from our study cycling between their two isomers in the sunlight. Read the full text of the article at 10.1002/chem.202400482.

Highly Ordered Co-Assembly of Bisurea Functionalized Molecular Switches at the Solid-Liquid Interface.

Immobilization of stimulus-responsive systems on solid surfaces is beneficial for controlled signal transmission and adaptive behavior while allowing the characterization of the functional interface with high sensitivity and high spatial resolution. Positioning of the stimuli-responsive units with nanometer-scale precision across the adaptive surface remains one of the bottlenecks in the extraction of cooperative function. Nanoscale organization, cooperativity, and amplification remain key challenges in bridging the molecular and the macroscopic worlds. Here we report on the design, synthesis, and scanning tunneling microscopy (STM) characterization of overcrowded alkene photoswitches merged in self-assembled networks physisorbed at the solid-liquid interface. A detailed anchoring strategy that ensures appropriate orientation of the switches with respect to the solid surface through the use of bis-urea groups is presented. We implement a co-assembly strategy that enables the merging of the photoswitches within physisorbed monolayers of structurally similar 'spacer' molecules. The self-assembly of the individual components and the co-assemblies was examined in detail using (sub)molecular resolution STM which confirms the robust immobilization and controlled orientation of the photoswitches within the spacer monolayers. The experimental STM data is supported by detailed molecular mechanics (MM) simulations. Different designs of the switches and the spacers were investigated which allowed us to formulate guidelines that enable the precise organization of the photoswitches in crystalline physisorbed self-assembled molecular networks.

Substituent effects on first generation photochemical molecular motors probed by femtosecond stimulated Raman.

Unidirectional photochemical molecular motors can act as a power source for molecular machines. The motors operate by successive excited state isomerization and ground state helix inversion reactions, attaining unidirectionality from an interplay of steric strain and stereochemistry. Optimizing the yield of the excited state isomerization reaction is an important goal that requires detailed knowledge of excited state dynamics. Here, we investigate the effect of electron withdrawing and donating substituents on excited state structure and ultrafast dynamics in a series of newly synthesized first generation photochemical molecular motors. All substituents red-shift the absorption spectra, while some modify the Stokes shift and render the fluorescence quantum yield solvent polarity dependent. Raman spectra and density functional theory calculations reveal that the stretching mode of the C=C "axle" in the electronic ground state shows a small red-shift when conjugated with electron withdrawing substituents. Ultrafast fluorescence measurements reveal substituent and solvent polarity effects, with the excited state decay being accelerated by both polar solvent environment and electron withdrawing substituents. Excited state structural dynamics are investigated by fluorescence coherence spectroscopy and femtosecond stimulated Raman spectroscopy. The time resolved Raman measurements are shown to provide structural data specifically on the Franck-Condon excited state. The C=C localized modes have a different substituent dependence compared to the ground state, with the unsubstituted motor having the most red-shifted mode. Such measurements provide valuable new insights into pathways to optimize photochemical molecular motor performance, especially if they can be coupled with high-quality quantum molecular dynamics calculations.

Enlightening dynamic functions in molecular systems by intrinsically chiral light-driven molecular motors.

Chirality is a fundamental property which plays a major role in chemistry, physics, biological systems and materials science. Chiroptical artificial molecular motors (AMMs) are a class of molecules which can convert light energy input into mechanical work, and they hold great potential in the transformation from simple molecules to dynamic systems and responsive materials. Taking distinct advantages of the intrinsic chirality in these structures and the unique opportunity to modulate the chirality on demand, chiral AMMs have been designed for the development of light-responsive dynamic processes including switchable asymmetric catalysis, chiral self-assembly, stereoselective recognition, transmission of chirality, control of spin selectivity and biosystems as well as integration of unidirectional motion with specific mechanical functions. This review focuses on the recently developed strategies for chirality-led applications by the class of intrinsically chiral AMMs. Finally, some limitations in current design and challenges associated with recent systems are discussed and perspectives towards promising candidates for responsive and smart molecular systems and future applications are presented.

A Multiresponsive Ferrocene-Based Chiral Overcrowded Alkene Twisting Liquid Crystals.

The reversible modulation of chirality has gained significant attention not only for fundamental stereochemical studies but also for numerous applications ranging from liquid crystals (LCs) to molecular motors and machines. This requires the construction of switchable molecules with (multiple) chiral elements in a highly enantioselective manner, which is often a significant synthetic challenge. Here, we show that the dimerization of an easily accessible enantiopure planar chiral ferrocene-indanone building block affords a multi-stimuli-responsive dimer (FcD) with pre-determined double bond geometry, helical chirality, and relative orientation of the two ferrocene motifs in high yield. This intrinsically planar chiral switch can not only undergo thermal or photochemical E/Z isomerization but can also be reversibly and quantitatively oxidized to both a monocationic and a dicationic state which is associated with significant changes in its (chir)optical properties. Specifically, FcD acts as a chiral dopant for cholesteric LCs with a helical twisting power (HTP) of 13 µm-1 which, upon oxidation, drops to near zero, resulting in an unprecedently large redox-tuning of the LC reflection color by up to 84 nm. Due to the straightforward stereoselective synthesis, FcD, and related chiral switches, are envisioned to be powerful building blocks for multi-stimuli-responsive molecular machines and in LC-based materials.

Photocleavable Protecting Groups Using a Sulfite Self-Immolative Linker for High Uncaging Quantum Yield and Aqueous Solubility.

Using light as an external stimulus to control (bio)chemical processes offers many distinct advantages. Most importantly, it allows for spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self-immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self-immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate-linked PPG. Furthermore, we demonstrate that uncaging of the sulfite-linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate-based systems.

Orthogonal Photoswitching in a Porous Organic Framework.

The development of photoresponsive systems with non-invasive orthogonal control by distinct wavelengths of light is still in its infancy. In particular, the design of photochemically triggered-orthogonal systems integrated into solid materials that enable multiple dynamic control over their properties remains a longstanding challenge. Here, we report the orthogonal and reversible control of two types of photoswitches in an integrated solid porous framework, that is, visible-light responsive o-fluoroazobenzene and nitro-spiropyran motifs. The properties of the constructed material can be selectively controlled by different wavelengths of light thus generating four distinct states providing a basis for dynamic multifunctional materials. Solid-state NMR spectroscopy demonstrated the selective transformation of the azobenzene switch in the bulk, which in turn modulates N2 and CO2 adsorption.