Stimulus-Controlled Anion Binding and Transport by Synthetic Receptors.

Anionic species are omnipresent and involved in many important biological processes. A large number of artificial anion receptors has therefore been developed. Some of these are capable of mediating transmembrane transport. However, where transport proteins can respond to stimuli in their surroundings, creation of synthetic receptors with stimuli-responsive functions poses a major challenge. Herein, we give a full overview of the stimulus-controlled anion receptors that have been developed thus far, including their application in membrane transport. In addition to their potential operation as membrane carriers, the use of anion recognition motifs in forming responsive membrane-spanning channels is discussed. With this review article, we intend to increase interest in transmembrane transport among scientists working on host-guest complexes and dynamic functional systems in order to stimulate further developments.

A Photoswitchable Macrocycle Controls Anion-Templated Pseudorotaxane Formation and Axle Relocalization.

Important biological processes, such as signaling and transport, are regulated by dynamic binding events. The development of artificial supramolecular systems in which binding between different components is controlled could help emulate such processes. Herein, we describe stiff-stilbene-containing macrocycles that can be switched between (Z)- and (E)-isomers by light, as demonstrated by UV/Vis and 1 H NMR spectroscopy. The (Z)-isomers can be effectively threaded by pyridinium halide axles to give pseudorotaxane complexes, as confirmed by 1 H NMR titration studies and single-crystal X-ray crystallography. The overall stability of these complexes can be tuned by varying the templating counteranion. However, upon light-induced isomerization to the (E)-isomer, the threading capability is drastically reduced. The axle component, in addition, can form a heterodimeric complex with a secondary isophthalamide host. Therefore, when all components are combined, light irradiation triggers axle exchange between the macrocycle and this secondary host, which has been monitored by 1 H NMR spectroscopy and simulated computationally.

Monodirectional Photocycle Drives Proton Translocation.

Photoisomerization of retinal is pivotal to ion translocation across the bacterial membrane and has served as an inspiration for the development of artificial molecular switches and machines. Light-driven synthetic systems in which a macrocyclic component transits along a nonsymmetric axle in a specific direction have been reported; however, unidirectional and repetitive translocation of protons has not been achieved. Herein, we describe a unique protonation-controlled isomerization behavior for hemi-indigo dyes bearing N-heterocycles, featuring intramolecular hydrogen bonds. Light-induced isomerization from the Z to E isomer is unlocked when protonated, while reverse E → Z photoisomerization occurs in the neutral state. As a consequence, associated protons are displaced in a preferred direction with respect to the photoswitchable scaffold. These results will prove to be critical in developing artificial systems in which concentration gradients can be effectively generated using (solar) light energy.

Photoswitchable Bis(amidopyrroles): Modulating Anion Transport Activity Independent of Binding Affinity.

Toward photocontrol of anion transport across the bilayer membrane, stiff-stilbene, which has dimethyl substituents in the five-membered rings, is functionalized with amidopyrrole units. UV-vis and 1H NMR studies show high photostability and photoconversion yields. Where the photoaddressable (E)- and (Z)-isomers exhibit comparable binding affinities, as determined by 1H NMR titrations, fluorescence-based transport assays reveal significantly higher transport activity for the (Z)-isomers. Changing the binding affinity is thus not a necessity for modulating transport. Additionally, transport can be triggered in situ by light.

Photomodulation of Transmembrane Transport and Potential by Stiff-Stilbene Based Bis(thio)ureas.

Membrane transport proteins fulfill important regulatory functions in biology with a common trait being their ability to respond to stimuli in the environment. Various small-molecule receptors, capable of mediating transmembrane transport, have been successfully developed. However, to confer stimuli-responsiveness on them poses a fundamental challenge. Here we demonstrate photocontrol of transmembrane transport and electric potential using bis(thio)ureas derived from stiff-stilbene. UV-vis and 1H NMR spectroscopy are used to monitor E-Z photoisomerization of these bis(thio)ureas and 1H NMR titrations reveal stronger binding of chloride to the (Z)-form than to the (E)-form. Additional insight into the binding properties is provided by single crystal X-ray crystallographic analysis and DFT geometry optimization. Importantly, the (Z)-isomers are much more active in transmembrane transport than the respective (E)-isomers as shown through various assays. As a result, both membrane transport and depolarization can be modulated upon irradiation, opening up new prospects toward light-based therapeutics as well as physiological and optopharmacological tools for studying anion transport-associated diseases and to stimulate neuronal activity, respectively.

From Photoinduced Supramolecular Polymerization to Responsive Organogels.

Controlling supramolecular polymerization by external stimuli holds great potential toward the development of responsive soft materials and manipulating self-assembly at the nanoscale. Photochemical switching offers the prospect of regulating the structure and properties of systems in a noninvasive and reversible manner with spatial and temporal control. In addition, this approach will enhance our understanding of supramolecular polymerization mechanisms; however, the control of molecular assembly by light remains challenging. Here we present photoresponsive stiff-stilbene-based bis-urea monomers whose trans isomers readily form supramolecular polymers in a wide range of organic solvents, enabling fast light-triggered depolymerization-polymerization and reversible gel formation. Due to the stability of the cis isomers and the high photostationary states (PSS) of the cis-trans isomerization, precise control over supramolecular polymerization and in situ gelation could be achieved with short response times. A detailed study on the temperature-dependent and photoinduced supramolecular polymerization in organic solvents revealed a kinetically controlled nucleation-elongation mechanism. By application of a Volta phase plate to enhance the phase-contrast method in cryo-EM, unprecedented for nonaqueous solutions, uniform nanofibers were observed in organic solvents.

Push-Pull Stiff-Stilbene: Proton-Gated Visible-Light Photoswitching and Acid-Catalyzed Isomerization.

Donor-acceptor substituted stiff-stilbene is shown to undergo isomerization induced by visible light avoiding the need for harmful UV light. This visible-light photoswitching is inhibited by protonation of the dimethylamino-donor unit, disrupting the push-pull character and thus, gating of the photochromic properties is allowed by acid/base addition. Remarkably, the addition of a mild acid also triggers fast thermal back-isomerization, which is unprecedented for stiff-stilbene photoswitches usually having a very high energy barrier for this process. These combined features offer unique orthogonal control over switching behavior by light and protonation, which is investigated in detail by 1 H NMR and UV/Vis spectroscopy. In addition, TD-DFT calculations are used to gain further insight into the absorption properties. Our results will help elevating the level of control over dynamic behavior in stiff-stilbene applications.

Tuning of Morphology by Chirality in Self-Assembled Structures of Bis(Urea) Amphiphiles in Water.

We present the synthesis and self-assembly of a chiral bis(urea) amphiphile and show that chirality offers a remarkable level of control towards different morphologies. Upon self-assembly in water, the molecular-scale chiral information is translated to the mesoscopic level. Both enantiomers of the amphiphile self-assemble into chiral twisted ribbons with opposite handedness, as supported by Cryo-TEM and circular dichroism (CD) measurements. The system presents thermo-responsive aggregation behavior and combined transmittance measurements, temperature-dependent UV, CD, TEM, and micro-differential scanning calorimetry (DSC) show that a ribbon-to-vesicles transition occurs upon heating. Remarkably, chirality allows easy control of morphology as the self-assembly into distinct aggregates can be tuned by varying the enantiomeric excess of the amphiphile, giving access to flat sheets, helical ribbons, and twisted ribbons.

Molecular rotary motors: Unidirectional motion around double bonds.

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

Controlled Diffusion of Photoswitchable Receptors by Binding Anti-electrostatic Hydrogen-Bonded Phosphate Oligomers.

Dihydrogen phosphate anions are found to spontaneously associate into anti-electrostatic oligomers via hydrogen bonding interactions at millimolar concentrations in DMSO. Diffusion NMR measurements supported formation of these oligomers, which can be bound by photoswitchable anion receptors to form large bridged assemblies of approximately three times the volume of the unbound receptor. Photoisomerization of the oligomer-bound receptor causes a decrease in diffusion coefficient of up to 16%, corresponding to a 70% increase in effective volume. This new approach to external control of diffusion opens prospects in controlling molecular transport using light.

Stiff-Stilbene Photoswitches: From Fundamental Studies to Emergent Applications.

Stiff-stilbene, a sterically restricted fused ring analogue of stilbene, has been regularly used as a model compound in theoretical studies of stilbene photoisomerization. Lately, owing to its excellent photoswitching properties, it is increasingly being applied to reversibly control the properties and function of chemical as well as biological systems. Stiff-stilbene photoswitches possess a number of advantageous properties including a high quantum yield for photoisomerization and a high thermal stability. Furthermore, they undergo a large geometrical change upon isomerization and their synthesis is straightforward. Herein, we provide an overview of the basic properties of stiff-stilbene and of recent applications in supramolecular chemistry, catalysis, and biological systems.

Visible-Light-Driven Tunable Molecular Motors Based on Oxindole.

Molecular rotary motors based on oxindole which can be driven by visible light are presented. This novel class of motors can be easily synthesized via a Knoevenagel condensation, and the choice of different upper halves allows for the facile tuning of their rotational speed. The four-step rotational cycle was explored using DFT calculations, and the expected photochemical and thermal isomerization behavior was confirmed by NMR, UV/vis, and CD spectroscopy. These oxindole motors offer attractive prospects for functional materials responsive to light.

Light-Modulated Self-Blockage of a Urea Binding Site in a Stiff-Stilbene Based Anion Receptor.

Anion binding to a receptor based on stiff-stilbene, which is equipped with a urea hydrogen bond donating group and a phosphate or phosphinate hydrogen bond accepting group, can be controlled by light. In one photoaddressable state (E isomer) the urea binding site is available for binding, while in the other (Z isomer) it is blocked because of an intramolecular interaction with its hydrogen bond accepting motif. This intramolecular interaction is supported by DFT calculations and 1 H NMR titrations reveal a significantly lower anion binding strength for the state in which anion binding is blocked. Furthermore, the molecular switching process has been studied in detail by UV/Vis and NMR spectroscopy. The presented approach opens up new opportunities toward the development of photoresponsive anion receptors.

Salen-Based Amphiphiles: Directing Self-Assembly in Water by Metal Complexation.

Tuning morphologies of self-assembled structures in water is a major challenge. Herein we present a salen-based amphiphile which, using complexation with distinct transition metal ions, allows to control effectively the self-assembly morphology in water, as observed by Cryo-TEM and confirmed by DLS measurements. Applying this strategy with various metal ions gives a broad spectrum of self-assembled structures starting from the same amphiphilic ligand (from cubic structures to vesicles and micelles). Thermogravimetric analysis and electric conductivity measurements reveal a key role for water coordination apparently being responsible for the distinct assembly behavior.

A chiral self-sorting photoresponsive coordination cage based on overcrowded alkenes.

In recent years, increasing efforts have been devoted to designing new functional stimuli-responsive supramolecular assemblies. Here, we present three isomeric supramolecular coordination complexes consisting of a Pd2L4 stoichiometry. As shown by NMR, CD and X-ray studies, as well as DFT calculations, these complexes form cage-like structures by chiral self-sorting. Photochromic ligands derived from first generation molecular motors enable light-driven interconversion between the three isomers. Two of the isomers were able to form host-guest complexes opening up new prospects toward stimuli-controlled substrate binding and release.

Braking of a Light-Driven Molecular Rotary Motor by Chemical Stimuli.

Artificial molecular motors hold great promise for application in responsive functional materials as well as to control the properties of biohybrid systems. Herein a strategy is reported to modulate the rotation of light-driven molecular motors. That is, the rotary speed of a molecular motor, functionalized with a biphenol moiety, could be decreased in situ by non-covalent substrate binding, as was established by 1 H NMR and UV/Vis spectroscopy. These findings constitute an important step in the development of multi-responsive molecular machinery.

Light-Gated Rotation in a Molecular Motor Functionalized with a Dithienylethene Switch.

A multiphotochromic hybrid system is presented in which a light-driven overcrowded alkene-based molecular rotary motor is connected to a dithienylethene photoswitch. Ring closing of the dithienylethene moiety, using an irradiation wavelength different from the wavelength applied to operate the molecular motor, results in inhibition of the rotary motion as is demonstrated by detailed 1 H-NMR and UV/Vis experiments. For the first time, a light-gated molecular motor is thus obtained. Furthermore, the excitation wavelength of the molecular motor is red-shifted from the UV into the visible-light region upon attachment of the dithienylethene switch.

Asymmetric Synthesis of Second-Generation Light-Driven Molecular Motors.

The enantiomeric homogeneity of light-driven molecular motors based on overcrowded alkenes is crucial in their application as either unidirectional rotors or as chiral multistate switches. It was challenging to obtain these compounds as single enantiomers via the established synthetic procedures due to loss of optical purity in the key step, i.e., the Barton-Kellogg olefination reaction. Searching for strategies to avoid racemization, a new class of light-driven molecular motors was designed, synthesized, and studied. The stereochemical integrity was fully preserved throughout the synthesis, and on the basis of photochemical and kinetic studies using UV/vis, CD, and 1H NMR spectroscopy, it was established that they still function properly as unidirectional molecular motors.

Unraveling the Photoswitching Mechanism in Donor-Acceptor Stenhouse Adducts.

Molecular photoswitches have opened up a myriad of opportunities in applications ranging from responsive materials and control of biological function to molecular logics. Here, we show that the photoswitching mechanism of donor-acceptor Stenhouse adducts (DASA), a recently reported class of photoswitches, proceeds by photoinduced Z-E isomerization, followed by a thermal, conrotatory 4π-electrocyclization. The photogenerated intermediate is manifested by a bathochromically shifted band in the visible absorption spectrum of the DASA. The identification of the role of this intermediate reveals a key step in the photoswitching mechanism that is essential to the rational design of switching properties via structural modification.

Allosteric Regulation of the Rotational Speed in a Light-Driven Molecular Motor.

The rotational speed of an overcrowded alkene-based molecular rotary motor, having an integrated 4,5-diazafluorenyl coordination motif, can be regulated allosterically via the binding of metal ions. DFT calculations have been used to predict the relative speed of rotation of three different (i.e., zinc, palladium, and platinum) metal dichloride complexes. The photochemical and thermal isomerization behavior of these complexes has been studied in detail using UV-vis and 1H NMR spectroscopy. Our results confirm that metal coordination induces a contraction of the diazafluorenyl lower half, resulting in a reduction of the steric hindrance in the "fjord" region of the molecule, which causes an increase of the rotational speed. Importantly, metal complexation can be accomplished in situ and is found to be reversible upon the addition of a competing ligand. Consequently, the rotational behavior of these molecular motors can be dynamically controlled with chemical additives.