The field of photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. It aims to reduce systemic drug toxicity and the emergence of resistance, while achieving unprecedented precision in treatment. By using small molecules, photopharmacology provides a viable alternative to optogenetics. We present here a critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner. We discuss the prospects for the selective delivery of light to these organs and the specific requirements for light-activatable drugs. We also aim to illustrate the druggability of medicinal targets with recent findings and emphasize where conceptually new approaches have to be explored to provide photopharmacology with future opportunities to bring "smart" molecular design ultimately to the realm of clinical use.

Photocleavable protecting groups (PPGs) are extensively used in chemical and biological sciences. In their application, advantage is taken of using light as an external, non-invasive stimulus, which can be delivered with very high spatiotemporal precision. More recently, orthogonally addressing multiple PPGs, in a single system and with different wavelengths of light, has been explored. This approach allows one to independently control multiple functionalities in an external, non-invasive fashion. In this tutorial review, we discuss the design principles for dynamic systems involving wavelength-selective deprotection, focusing on the choice and optimization of PPGs, synthetic methods for their introduction and strategies for combining multiple PPGs into one system. Finally, we illustrate the design principles with representative examples, aiming at providing the reader with an instructive overview on how the wavelength-selective cleavage of photoprotecting groups can be applied in materials science, organic synthesis and biological systems.

Molecular photoswitches comprise chromophores that can be interconverted reversibly with light between two states with different photochemical and physicochemical properties. This feature renders them useful for diverse applications, ranging from materials science, biology (specifically photopharmacology) to supramolecular chemistry. With new and more challenging systems to control, especially extending towards biomedical applications, using visible or near-infrared light for photoswitch activation becomes vital. Donor-acceptor Stenhouse adducts are a novel class of visible light-responsive negative photochromes that provide a possible answer to current limitations of other photoswitch classes in the visible and NIR window. Their rapid development since their discovery in 2014, together with first successful examples of applications, demonstrate both their potential and areas where improvements are needed. A better understanding of DASA characteristics and its photoswitching mechanism has revealed that they are in fact a subset of a more general structural class of photochromes, namely Stenhouse photoswitches. This tutorial review aims at providing an introduction and practical guide on DASAs: it focuses on their structure and synthesis, provides fundamental insights for understanding their photoswitching behavior and demonstrates guiding principles for tailoring these switches for given applications.

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.

The wavelength-selective, reversible photocontrol over various molecular processes in parallel remains an unsolved challenge. Overlapping ultraviolet-visible spectra of frequently employed photoswitches have prevented the development of orthogonally responsive systems, analogous to those that rely on wavelength-selective cleavage of photo-removable protecting groups. Here we report the orthogonal and reversible control of two distinct types of photoswitches in one solution, that is, a donor–acceptor Stenhouse adduct (DASA) and an azobenzene. The control is achieved by using three different wavelengths of irradiation and a thermal relaxation process. The reported combination tolerates a broad variety of differently substituted photoswitches. The presented system is also extended to an intramolecular combination of photoresponsive units. A model application for an intramolecular combination of switches is presented, in which the DASA component acts as a phase-transfer tag, while the azobenzene moiety independently controls the binding to α-cyclodextrin.

Donor–acceptor Stenhouse adducts (DASAs) are negative photochromes that hold great promise for a variety of applications. Key to optimizing their switching properties is a detailed understanding of the photoswitching mechanism, which, as yet, is absent. Here we characterize the actinic step of DASA-photoswitching and its key intermediate, which was studied using a combination of ultrafast visible and IR pump–probe spectroscopies and TD-DFT calculations. Comparison of the time-resolved IR spectra with DFT computations allowed to unambiguously identify the structure of the intermediate, confirming that light absorption induces a sequential reaction path in which a Z–E photoisomerization of C2–C3 is followed by a rotation around C3–C4 and a subsequent thermal cyclization step. First and second-generation DASAs share a common photoisomerization mechanism in chlorinated solvents with notable differences in kinetics and lifetimes of the excited states. The photogenerated intermediate of the second-generation DASA was photo-accumulated at low temperature and probed with time-resolved spectroscopy, demonstrating the photoreversibility of the isomerization process. Taken together, these results provide a detailed picture of the DASA isomerization pathway on a molecular level.

Switches that can be actively steered by external stimuli along multiple pathways at the molecular level are the basis for next-generation responsive material systems. The operation of commonly employed molecular photoswitches revolves around one key structural coordinate. Photoswitches with functionalities that depend on and can be addressed along multiple coordinates would offer novel means to tailor and control their behavior and performance. The recently developed donor–acceptor Stenhouse adducts (DASAs) are versatile switches suitable for such applications. Their photochemistry is well understood, but is only responsible for part of their overall photoswitching mechanism. The remaining thermal switching pathways are to date unknown. Here, rapid-scan infrared absorption spectroscopy is used to obtain transient fingerprints of reactions occurring on the ground state potential energy surface after reaching structures generated through light absorption. The spectroscopic data are interpreted in terms of structural transformations using kinetic modeling and quantum chemical calculations. Through this combined experimental–theoretical approach, we are able to unravel the complexity of the multidimensional ground-state potential energy surface explored by the photoswitch and use this knowledge to predict, and subsequently confirm, how DASA switches can be guided along this potential energy surface. These results break new ground for developing user-geared DASA switches but also shed light on the development of novel photoswitches in general.

Donor–acceptor Stenhouse adducts (DASAs) are negative photochromes that switch with visible light and are highly promising for applications ranging from smart materials to biological systems. However, the strong solvent dependence of the photoswitching kinetics limits their application. The nature of the photoswitching mechanism in different solvents is key for addressing the solvatochromism of DASAs, but as yet has remained elusive. Here, we employ spectroscopic analyses and TD‐DFT calculations to reveal changing solvatochromic shifts and energies of the species involved in DASA photoswitching. Time‐resolved visible pump‐probe spectroscopy suggests that the primary photochemical step remains the same, irrespective of the polarity and protic nature of the solvent. Disentangling the different factors determining the solvent‐dependence of DASA photoswitching, presented here, is crucial for the rational development of applications in a wide range of different media.