In this paper we elaborate on recently developed molecular switch architectures and how these new systems can help with the realization of new functions and advancement of artificial molecular machines. Progress in chemically and photoinduced switches and motors is summarized and contextualized such that the reader may gain an appreciation for the novel tools that have come about in the past decade. Many of these systems offer distinct advantages over commonly employed switches, including improved fidelity, addressability, and robustness. Thus, this paper serves as a jumping-off point for researchers seeking new switching motifs for specific applications, or ones that address the limitations of presently available systems.

https://www.pnas.org/content/pnas/115/38/9414.full.pdf

New molecular switch architectures

Molecular photoswitches enable dynamic control of processes with high spatiotemporal precision, using light as external stimulus, and hence are ideal tools for different research areas spanning from chemical biology to smart materials. Photoswitches are typically organic molecules that feature extended aromatic systems to make them responsive to (visible) light. However, this renders them inherently lipophilic, while water-solubility is of crucial importance to apply photoswitchable organic molecules in biological systems, like in the rapidly emerging field of photopharmacology. Several strategies for solubilizing organic molecules in water are known, but there are not yet clear rules for applying them to photoswitchable molecules. Importantly, rendering photoswitches water-soluble has a serious impact on both their photophysical and biological properties, which must be taken into consideration when designing new systems. Altogether, these aspects pose considerable challenges for successfully applying molecular photoswitches in aqueous systems, and in particular in biologically relevant media. In this review, we focus on fully water-soluble photoswitches, such as those used in biological environments, in both in vitro and in vivo studies. We discuss the design principles and prospects for water-soluble photoswitches to inspire and enable their future applications.

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Molecular photoswitches in aqueous environments

Diazocines are bridged azobenzenes with superior photophysical properties. In contrast to azobenzenes the Z configuration is thermodynamically stable and the E isomer is metastable. We present a new class of nitrogen bridged diazocines with bathochromically shifted switching wavelengths and remarkably high quantum yields (-NH-CH2- bridged diazocine: ΦZ→E = 0.57, ΦE→Z = 0.8). Z to E isomerization is induced by irradiation with blue light, whereas switching back to the Z isomer is accomplished with light in the near-infrared window (up to 740 nm), which is important for medical applications like photopharmacology (deep tissue penetration). Furthermore, substitution at the bridging nitrogen should provide access to widely applicable tricyclic, photoswitchable pharmacophores. The -NAc-CH2- bridged derivative is soluble in water, and all photophysical properties (conversion rates, quantum yields, and thermal half-lives) are largely retained. Hence, this diazocine is an ideal photoswitch for applications in biochemical systems and in photopharmacology.

Nitrogen Bridged Diazocines: Photochromes Switching within the Near-Infrared Region with High Quantum Yields in Organic Solvents and in Water

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

Chemical vapour deposition (CVD) enables nanoscale control for the synthesis of high-purity polymer thin films. Ultrathin (<20 nm) and ultrasmooth (<1 nm r.m.s. roughness) layers of CVD polymers can conform to the geometry of the growth surface. This Review focuses on CVD polymerization methods adapted from solution chemistry for selectively forming different classes of macromolecules. The mechanistically based CVD approaches provide full retention of the monomer’s organic functional groups and thus provide a rational basis for designing and optimizing film characteristics for a diverse array of applications. These include conjugated polymers for energy storage, thin dielectrics for low-power, flexible devices and responsive hydrogels for controlled drug release. Systematic variation in the CVD process parameters provides remarkable control of π–π stacking in conducting polymers, mesh sizes in hydrogels, crystallographic texture, surface energy, permeation rates of molecules and ions, optoelectronic properties and switchable smart behaviour. The initial research focus on process fundamentals, including adsorption, reaction kinetics, mass transport and conformality, formed a strong basis for the recent rapid expansion of materials, applications and scale-up activities in multiple laboratories. The materials and approaches used in CVD polymerization are also extending into hybrid inorganic/organic materials and devices. Chemical vapour deposition (CVD) enables the synthesis of high-purity, pinhole-free and conformal polymer thin films. This Review discusses the recent breakthroughs in mechanistically based CVD polymerization processes and designing CVD polymers for a diverse array of applications.

/pdf/nanoscale-control-by-chemically-vapour-deposited-polymers-e4xi9ciclx.pdf

Nanoscale control by chemically vapour-deposited polymers

Stimuli-responsive coordination cages allow reversible control over guest binding and release, relevant for adaptive receptors, carriers, catalysts, and complex systems. Light serves as an advantageous stimulus, as it can be applied with precise spatial and temporal resolution without producing chemical waste products. We report the first Pd-mediated coordination cage based on ligands embedding a diazocine photoswitch. While the thermodynamically more stable cis-photoisomer sloppily assembles to a mixture of species with general formula [Pdncis-L2n], the less stable trans-isomer yields a defined [Pd2trans-L4] cage that reversibly converts back to the cis-system by irradiation at 530 nm or thermal relaxation. The [Pdncis-L2n] species do not bind a given guest; however, [Pd2trans-L4] is able to encapsulate a bis-sulfonate as long as it is kept assembled, requiring continuous irradiation at 385 nm. In the absence of UV light, thermal relaxation results in back-switching and guest release. Assembly and properties of the system were characterized by a combination of NMR, ion mobility ESI-MS, single-crystal X-ray diffraction, and UV–vis absorption studies.

https://pubs.acs.org/doi/pdf/10.1021/jacs.1c12011

Light-Powered Dissipative Assembly of Diazocine Coordination Cages

http://diposit.ub.edu/dspace/bitstream/2445/147235/1/L01_2019_Organic%20Letters_21_3780_OA.pdf

Synthetic Photoswitchable Neurotransmitters Based on Bridged Azobenzenes.

A convenient two-step synthesis of diazocine starting from 2-nitrotoluene is described. The first step, the oxidative dimerization of 2-nitrotoluene, is improved to 95% yield. The second step, the reductive azo cyclization, is performed as a solvent-free reaction with lead powder in a ball mill (51% yield). As a reference, the previously described azo cyclization with Zn/Ba(OH) 2 is investigated in detail. The results explain why in previous experiments the yields are low and extremely dependent on the reaction conditions. In view of potential applications in photopharmacology, we checked the stability under reducing conditions. Diazocine does not react with glutathione, indicating intracellular stability.

Solvent-Free Synthesis of Diazocine

Seven symmetrically 3,3'-substituted diazocines were synthesized. Functional groups include alcohol, azide, amine and vinyl groups, which are suitable for polymer synthesis. Upon irradiation at 385 and 530 nm the diazocines perform a reversible, pincer-type movement switching the 3,3'-distance between 6.1 A (cis, stable isomer) and 8.2 A (trans, metastable isomer). Key reactions in the synthesis are an oxidative C-C coupling of 2-nitrotoluenes (75-82% yield) and a reductive ring closure to form the diazocines (56-60% yield). The cyclization of the dinitro compound to the azo compound was improved in yield and reproducibility, by over-reduction to the hydrazine and reoxidation to the azo unit. In contrast to 3,3'- and 4,4'-diaminodiazocine, which have been implemented in macromolecules for conformation switching, our compounds exhibit improved photophysical properties (photostationary states, separation of absorption bands in the cis and trans configuration). Hence they are promising candidates as molecular switches in photo and mechanoresponsive macromolecules and other smart materials.

https://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-15-68.pdf

Synthesis of functionalized diazocines for application as building blocks in photo- and mechanoresponsive materials

In this work, we demonstrate the first synthesis of photochromic polymer thin films via initiated chemical vapor deposition (iCVD) using bifunctional, crystalline styrenediazocine as a photochromic unit. Since it represents a solid compound, an innovative custom-made sublimation unit is introduced, which allows the sublimation of the chromophore as well as its transport inside the reactor chamber, maintaining the functionality of the photoswitch. Styrenediazocine was co-polymerized with 1,3,5-trivinyl-1,3,5-trimethylcyclotrisiloxane (V₃D₃), a heterocycle with triple vinyl functionality, in a radical polymerization reaction from the gas phase. The structural as well as functional properties of the resulting films were characterized by various methods, including X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared (FT-IR) spectroscopy, and UV–vis spectroscopy. It could be confirmed that, via iCVD, photoswitchable polymer thin films have been obtained. The polymer is based on a copolymer structure where all photoswitchable molecules are covalently bonded in the main polymer chain. Our approach could pave the way for a completely new class of high-quality, photochromic thin films that are basically applicable on almost every kind of substrate for novel, interdisciplinary application fields, where particularly classical wet chemistry methods cannot be applied.

Daniel Langbehn

Papers

Light-Powered Dissipative Assembly of Diazocine Coordination Cages

Synthetic Photoswitchable Neurotransmitters Based on Bridged Azobenzenes.

Solvent-Free Synthesis of Diazocine

Synthesis of functionalized diazocines for application as building blocks in photo- and mechanoresponsive materials

Fabrication of Diazocine-Based Photochromic Organic Thin Films via Initiated Chemical Vapor Deposition