Directionality Reversal and Shift of Rotational Axis in a Hemithioindigo Macrocyclic Molecular Motor.

Molecular motors are central driving units for nanomachinery, and control of their directional motions is of fundamental importance for their functions. Light-driven variants use easy to provide, easy to dose, and waste-free fuel with high energy content, making them particularly interesting for applications. Typically, light-driven molecular motors work via rotations around dedicated chemical bonds where the directionality of the rotation is dictated by the steric effects of asymmetry in close vicinity to the rotation axis. In this work, we show how unidirectional rotation around a virtual axis can be realized by reprogramming a molecular motor. To this end, a classical light-driven motor is restricted by macrocyclization, and its intrinsic directional rotation is transformed into a directional rotation of the macrocyclic chain in the opposite direction. Further, solvent polarity changes allow to toggle the function of this molecular machine between a directional motor and a nondirectional photoswitch. In this way, a new concept for the design of molecular motors is delivered together with elaborate control over their motions and functions by simple solvent changes. The possibility of sensing the environmental polarity and correspondingly adjusting the directionality of motions opens up a next level of control and responsiveness to light-driven nanoscopic motors.

Reversible C═N Bond Formation Controls Charge-Separation in an Aza-Diarylethene Photoswitch.

Diarylethenes belong to the most eminent photoswitches and have been studied for many decades. They are found in virtually every field of application and have become highly valuable molecular tools for instilling light-responsiveness into materials, catalysts, biological systems, or pharmacology. In this work, we present a novel and distinct type of pyrimidine-based aza-diarylethene, which undergoes a highly unusual zwitterion-forming photoreaction. During this fully reversible process, a CN double bond is established under concomitant aromatization and thiophene-ring opening. The metastable zwitterion thus possesses a positively charged extended aromatic structure and an independent conjugated thiolate function. It can further photoisomerize between a more stable Z and a less stable E isomer, resulting in effective four-state photoswitching. Unusual for diarylethenes, the metastable isomers show negative solvatochromism and red-shifted absorption in apolar solvents. With this behavior, aza-diarylethenes effectively bridge the properties of merocyanines and diarylethenes. Thermal stability of the zwitterions can be modulated from very labile to highly stable behavior in response to pH, again in a fully reversible manner. Pyrimidine-based aza-diarylethene thus establishes a unique photoreaction mechanism for diarylethenes, allowing control of charge separation, thermal stability, and color generation in a different way than hitherto possible.

Rhodanine-Based Chromophores: Fast Access to Capable Photoswitches and Application in Light-Induced Apoptosis.

Molecular photoswitches are highly desirable in all chemistry-related areas of research. They provide effective outside control over geometric and electronic changes at the nanoscale using an easy to apply, waste-free stimulus. However, simple and effective access to such molecular tools is typically not granted, and elaborate syntheses and substitution schemes are needed in order to obtain efficient photoswitching properties. Here we present a series of rhodanine-based photoswitches that can be prepared in one simple synthetic step without requiring elaborate purification. Photoswitching is induced by UV and visible light in both switching directions, and thermal stabilities of the metastable states as well as quantum yields are very high. An additional benefit is the hydrogen-bonding capacity of the rhodanine fragment, which enables applications in supramolecular or medicinal chemistry. We further show that the known rhodanine-based inhibitor SMI-16a is a photoswitchable apoptosis inducer. The biological activity of SMI-16a can effectively be switched ON or OFF by reversible photoisomerization between the inactive E and the active Z isomer. Rhodanine-based photoswitches therefore represent an easy to access and highly valuable molecular toolbox for implementing light responsiveness to the breadth of functional molecular systems.

Azotriptycenes: Photoswitchable Molecular Brakes.

The control of molecular motions is a central topic of molecular machine research. Molecular brakes are fundamental building blocks towards such goal as they allow deliberately decelerating specific motions after an outside stimulus is applied. Here we present azotriptycenes as structural framework for light-controlled molecular brakes. The intrinsic kinetics and their changes upon azotriptycene isomerization are scrutinized comprehensively by a mixed theoretical and variable temperature NMR approach. With azotriptycenes C-N bond rotation rates can be decelerated or accelerated reversibly by up to five orders of magnitude. Rate change effects are highly localized and are strongest for the C-N bond connecting a triptycene rotor fragment to the central diazo group. The detailed mechanistic insights provide a solid basis for further conscious design and applications in the future.

Second Generation Zwitterionic Aza-Diarylethene: Photoreversible CN Bond Formation, Three-State Photoswitching, Thermal Energy Release, and Facile Photoinitiation of Polymerization.

Diarylethenes are a well-studied and optimized class of photoswitches with a wide range of applications, including data storage, smart materials, or photocontrolled catalysis and biological processes. Most recently, aza-diarylethenes have been developed in which carbon-carbon bond connections are replaced by carbon-nitrogen connections. This structural elaboration opens an entire new structure and property space expanding versatility and applicability of diarylethenes. In this work, we present the second generation of zwitterionic aza-diarylethenes, which finally allows for fully reversible photoswitching and precise control over all three switching states. High-yielding photoswitching between the neutral open form and a zwitterionic Z isomer is achieved with two different wavelengths of light. The third zwitterionic E isomeric state can be reached up to 87% upon irradiation with a third wavelength. Its high energy content of >10 kcal/mol can be released thermally by deliberate solvent change as trigger mechanism, rendering aza-diarylethenes into interesting candidates for molecular solar thermal energy storage (MOST) applications. The third state further serves as locking state, allowing to toggle light-responsiveness reversibly between thermally labile and thermally stable switching. Further, irradiation of the zwitterionic states leads to highly efficient photopolymerization of methyl acrylate (MA), directly harnessing the unleashed chemical reactivity of aza-diarylethene in materials applications.

Path-Independent All-Visible Orthogonal Photoswitching for Applications in Multi-Photochromic Polymers and Molecular Computing.

Synthetic molecular photoswitches have taken center stage as high-precision tools to introduce light-responsiveness at the smallest scales. Today they are found in all areas of applied chemistry, covering materials research, chemical biology, catalysis, or nanotechnology. For a next step of applicability truly orthogonal photoswitching is highly desirable but to date such independent addressability of different photoswitches remains highly challenging. Herein we present the first example of all-visible, all-light responsive, and path- independent orthogonal photoswitching. By combining two recently developed indigoid photoswitches - peri-anthracenethioindigo and a rhodanine-based chromophore - a four-state system is established and each state can be accessed in high yields completely independently and also with visible light irradiation only. The four states give rise to four different colors, which can be transferred to a solid polymer matrix to yield a versatile multi-state photochromic material. Further, combination with a fluorescent dye as a third component is possible, demonstrating the applicability of this orthogonal photoswitching system in all-photonic molecular logic behavior and information processing.

Gain of Function Recyclable Photoswitches: Reversible Simultaneous Substitution and Photochromism Generation.

The use of molecular photoswitches has spread to virtually every field of pure and applied chemistry because of the extraordinary level of control they provide over the behavior of matter at the smallest scales. Photoswitches possess at least two different states with distinct structures and/or electronics and further functionalization of their core chromophore structures is needed to tailor them for a specific application. In this work we present a different concept for the generation and use of molecular photoswitches. It allows not only simultaneous establishment of photochromism and functionalization, but also full recyclability of a non-photochromic precursor material. Using a high-yielding and reversible ammonium salt formation, a functional group is introduced into a symmetric precursor while at the same time a strong electronic push-pull character is established in the structure. The resulting desymmetrization leads to efficient photoswitching capacity and the functional group can be fully removed subsequently by a simple heating step recovering the precursor for another functionalization round. We finally demonstrate feasibility of this concept over two consecutive closed loop functionalization/photoswitching/recovery steps. This concept offers great potential in any chemical research and application driven area but especially for the creation of responsive reprogrammable materials, no-background photoswitch labeling, and sustainable chemistry.

Directional Bias in Molecular Photogearing Evidenced by LED-Coupled Chiral Cryo-HPLC.

Molecular gearing systems are technomimetic nanoscale analogues to complex geared machinery in the macroscopic world. They are defined as systems incorporating intermeshed movable parts which perform correlated rotational motions by mechanical engagement. Only recently, new methods to actively drive molecular gearing motions instead of relying on passive thermal activation have been developed. Further progress in this endeavor will pave the way for unidirectional molecular gearing devices with a distinct type of molecular machine awaiting its realization. Within this work an essential step towards this goal is achieved by evidencing directional biases for the light-induced rotations in our molecular photogear system. Using a custom-designed LED-coupled chiral cryo-HPLC setup for the in situ irradiation of enantiomeric analytes, an intrinsic selectivity for clockwise or counterclockwise rotations was elucidated experimentally. Significant directional biases in the photogearing processes and light-induced single bond rotations (SBRs) are observed for our photogear with directional preferences of up to 4.8 : 1. Harnessing these effects will allow to rationally design and construct a fully directional molecular gearing motor in the future.

Defining Unidirectional Motions and Structural Reconfiguration in a Macrocyclic Molecular Motor.

The construction of sophisticated molecular machines requires not only precise control of energy fueled motions but their integration into larger functional architectures. Macrocyclization of molecular motors is a way to harness the intrinsic directionality of their rotation and use them to actively power different processes at the nano-scale. An effective concept in this regard uses a defined fragment of the molecular motor as a revolving door within the macrocycle. In this way, motor motions can be transmitted to distant structural entities, other rotations can be actively accelerated, or mechanical molecular threading events can be realized. In this work, a dual macrocyclization approach is presented, which not only allows to supersize the revolving door element but also structurally reconfigure the macrocycle in which the revolving door rotates. Unique possibilities for a multi-level precision control over integrated directional motions are thus opened up without deteriorating the functionality of the molecular machine.

Mechanistic Elucidation of the Hula-Twist Photoreaction in Hemithioindigo.

The Hula-Twist (HT) photoreaction represents a fundamental photochemical pathway for bond isomerizations and is defined by the coupled motion of a double bond and an adjacent single bond. This photoreaction has been suggested as the defining motion for a plethora of light-responsive chromophores such as retinal within opsins, coumaric acid within photoactive yellow protein, or vitamin D precursors, and stilbenes in solution. However, due to the fleeting character of HT photoproducts a direct experimental observation of this coupled molecular motion was severely hampered until recently. To solve this dilemma, the Dube group has designed a molecular framework able to deliver unambiguous experimental evidence of the HT photoreaction. Using sterically crowded atropisomeric hemithioindigo (HTI) the HT photoproducts are rendered thermally stable and can be observed directly after their formation. However, following the ultrafast excited state process of the HT photoreaction itself has not been achieved so far and thus crucial information for an elementary understanding is still missing. In this work, we present the first ultrafast spectroscopy study of the HT photoreaction in HTI and probe the competition between different excited state processes. Together with extensive excited state calculations a detailed mechanistic picture is developed explaining the significant solvent effects on the HT photoreaction and revealing the intricate interplay between productive isomerizations and unproductive twisted intramolecular charge transfer (TICT) processes. With this study essential insights are thus gained into the mechanism of complex multibond rotations in the excited state, which will be of primary importance for further developments in this field.

Peri-Anthracenethioindigo: A Scaffold for Efficient All-Red-Light and Near-Infrared Molecular Photoswitching.

Molecular photoswitching with red light is greatly desired to evade photodamage and achieve specific photoresponses. In virtually all reported cases however, only one switching direction uses red light while for the reverse switching, UV or visible light is needed. All-red-light photoswitching brings with it the clear advantage of pushing photoswitching to the limit of the low-energy spectrum, but no viable system is available currently. Here we report on peri-anthracenethioindigo (PAT) as molecular scaffold for highly efficient all-red-light photoswitching with an outstanding performance and property profile. The PAT photoswitch provides near-infrared (NIR) absorption up to 850 nm, large negative photochromism with more than 140 nm maxima shifts and changes color from green to blue upon irradiation with two shades of red light. Thermal stability of the metastable Z isomer is high with a corresponding half-life of days at 20 °C. Application in red-light responsive polymers undergoing pronounced and reversible green to blue color changes demonstrate spatially resolved photoswitching. The PAT photoswitch thus offers unique responsiveness to very low energy light together with predictable and large geometrical changes within a rigid molecular scaffold. We expect a plethora of applications for PAT in the near future, e.g. in materials, molecular machines or biological context.

Hemithioindigo-Based Trioxobicyclononadiene: 3D Multiswitching of Electronic and Geometric Properties.

Molecular photoswitches that offer simultaneous precise control over geometrical and electronic changes are rare yet highly sought tools for the development of responsive nanosystems. Here we present such an advantageous combination of property control within a novel multiphotoswitch architecture. Hemithioindigo-based trioxobicyclononadiene (HTI-TOND) offers a rigid three-dimensional molecular structure that undergoes different exotic rearrangement reactions upon photochemical and thermal signaling. Three to four different states with distinct geometric and electronic properties can be accessed reversibly in high yields within this molecular framework. Thus, a highly promising and unique switching tool has become available to instill the next level of addressability at the smallest scales.

An Eight-State Molecular Sequential Switch Featuring a Dual Single-Bond Rotation Photoreaction.

Typical photoswitches interconvert between two different states by simple isomerization reactions, which represents a fundamental limit for applications. To expand the switching capacity usually different photoswitches have to be linked together leading to strong increase in molecular weight, diminished switching function, and less precision and selectivity of switching events. Herein we present an approach for solving this essential problem with a different photoswitching concept. A basic molecular switch architecture provides precision photoswitching between eight different states via controlled rotations around three adjacent covalent bonds. All eight states can be populated one after another in an eight-step cycle by alternating between photochemical Hula-Twist isomerizations and thermal single-bond rotations. By simply changing solvent and temperature the same switch can also undergo a different cycle instead interconverting just five isomers in a selective sequence. This behavior is enabled through the discovery of an unprecedented photoreaction, a one-photon dual single-bond rotation.

Heterocyclic Hemithioindigos: Highly Advantageous Properties as Molecular Photoswitches.

A survey of heterocyclic hemithioindigo photoswitches is presented identifying a number of structural motives with outstanding property profiles. The highly sought-after combination of pronounced color change, quantitative switching in both directions, exceptional high quantum yields, and tunable high thermal stability of metastable states can be realized with 4-imidazole, 2-pyrrole, and 3-indole-based derivatives. In the former, an unusual preorganization using isomer selective chalcogen- and hydrogen bonding allows to precisely control geometry changes and tautomerism upon switching. Heterocyclic hemithioindigos thus represent highly promising photoswitches with advanced capabilities that will be of great value to anyone interested in establishing defined and reversible control at the molecular level.

Active Mechanical Threading by a Molecular Motor.

Molecular motors transform external energy input into directional motions and offer exquisite precision for nano-scale manipulations. To make full use of molecular motor capacities, their directional motions need to be transmitted and used for powering downstream molecular events. Here we present a macrocyclic molecular motor structure able to perform repetitive molecular threading of a flexible tetraethylene glycol chain through the macrocycle. This mechanical threading event is actively powered by the motor and leads to a direct translation of the unidirectional motor rotation into unidirectional translation motion (chain versus ring). The mechanism of the active mechanical threading is elucidated and the actual threading step is identified as a combined helix inversion and threading event. The established molecular machine function resembles the crucial step of macroscopic weaving or sewing processes and therefore offers a first entry point to a "molecular knitting" counterpart.

All-Red-Light Photoswitching of Indirubin Controlled by Supramolecular Interactions.

Red-light responsiveness of photoswitches is a highly desired property for many important application areas such as biology or material sciences. The main approach to elicit this property uses strategic substitution of long-known photoswitch motives such as azobenzenes or diarylethenes. Only very few photoswitches possess inherent red-light absorption of their core chromophore structures. Here, we present a strategy to convert the long-known purple indirubin dye into a prolific red-light-responsive photoswitch. In a supramolecular approach, its photochromism can be changed from a negative to a positive one, while at the same time, significantly higher yields of the metastable E-isomer are obtained upon irradiation. E- to Z-photoisomerization can then also be induced by red light of longer wavelengths. Indirubin therefore represents a unique example of reversible photoswitching using entirely red light for both switching directions.

Steric Effects on the Thermal Processes of Hemithioindigo Based Molecular Motor Rotation.

Tuning the thermal behavior of light driven molecular motors is fundamentally important for their future rational design. In many molecular motors thermal ratcheting steps are comprised of helicity inversions, energetically stabilizing the initial photoproducts. In this work we investigated a series of five hemithioindigo (HTI) based molecular motors to reveal the influence of steric hindrance in close proximity to the rotation axle on this process. Applying a high yielding synthetic procedure, we synthesized constitutional isomeric derivatives to distinguish between substitution effects at the aromatic and aliphatic position on the rotor fragment. The kinetics of thermal helix inversions were elucidated using low temperature 1 H NMR spectroscopy and an in situ irradiation technique. In combination with a detailed theoretical description, a comparative analysis of substituent effects on the thermal helix inversions of the rotation cycle is now possible. Such deeper understanding of the rotational cycle of HTI molecular motors is essential for speed regulation and future applications of visible light triggered nanomachines.

Electronic and Geometric Characterization of TICT Formation in Hemithioindigo Photoswitches by Picosecond Infrared Spectroscopy.

Deciphering the exact electronic and geometric changes of photoexcited molecules is an important task not only to understand the fundamental atomistic mechanisms but also to rationally design molecular properties and functions. Here, we present a combined experimental and theoretical study of the twisted intramolecular charge transfer (TICT) process in hemithioindigo photoswitches. Using ultrafast transient IR spectroscopy as the main analytical method, a detailed understanding of the extent and direction of charge transfer within the excited molecule is obtained. At the same time, the geometrical distortion is monitored directly via changes of indicative vibrational modes over the time course of the photoreaction. These high-resolution data deliver a detailed molecular movie of the TICT process in this important class of chromophores with picosecond time resolution.

Light-Controlled Cell-Cycle Arrest and Apoptosis.

Cell-cycle interference by small molecules has widely been used to study fundamental biological mechanisms and to treat a great variety of diseases, most notably cancer. However, at present only limited possibilities exist for spatio-temporal control of the cell cycle. Here we report on a photocaging strategy to reversibly arrest the cell cycle at metaphase or induce apoptosis using blue-light irradiation. The versatile proteasome inhibitor MG132 is photocaged directly at the reactive aldehyde function effectively masking its biological activity. Upon irradiation reversible cell-cycle arrest in the metaphase is demonstrated to take place in vivo. Similarly, apoptosis can efficiently be induced by irradiation of human cancer cells. With the developed photopharmacological approach spatio-temporal control of the cell cycle is thus enabled with very high modulation, as caged MG132 shows no effect on proliferation in the dark. In addition, full compatibility of photo-controlled uncaging with dynamic microscopy techniques in vivo is demonstrated. This visible-light responsive tool should be of great value for biological as well as medicinal approaches in need of high-precision targeting of the proteasome and thereby the cell cycle and apoptosis.

Supramolecular Relay-Control of Organocatalysis with a Hemithioindigo-Based Molecular Motor.

Integration of individual molecular components such as molecular motors or switches into larger meta-functional systems represents a current challenge at the forefront of molecular machine research. Here we present a modular supramolecular approach to relay the photoinduced geometry changes of a hemithioindigo based molecular motor into catalytic efficiency of a chemical reaction. Using the intrinsic chemical nature of the motor for recognition of different hydrogen-bonding organocatalysts a greater than 10-fold modulation in binding affinity is achieved upon photoisomerization. This change in affinity is then translated effectively into control of catalytic competence of the organocatalysts without direct interference by the motor. As an example the organocatalysed Michael addition reaction between nitrostyrene and 3-methoxy-dimethyl aniline was modulated in situ by visible light irradiation. Thus, dynamic and reversible remote control of catalytic processes by the switching capacity of a hemithioindigo molecular motor is established in a multicomponent chemical system. The high intrinsic modularity of this approach presents further advantages, e.g., for easy tailoring of conditions or facile exchange of catalysts and reactions. These results represent a first stepping stone into integrated chemical networks regulated by molecular machines in a fully dynamic way.