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Visible-light-operated photoswitches are of growing interest in reversibly controlling molecular processes, enabling for example the precise spatiotemporal focusing of drug activity and manipulating the properties of materials. Therefore, many research efforts have been spent on seeking control over the (photo)physical properties of photoswitches, in particular the absorption maxima and the half-life. For photopharmacological applications, photoswitches should ideally be operated by visible light in at least one direction, and feature a metastable isomer with a half-life of 0.1-10 seconds. Here we present our efforts towards the engineering of the half-life of iminothioindoxyl (ITI) photoswitches, a recently discovered class of visible-light-responsive photochromes, whose applicability was hitherto limited by half-lives in the low millisecond range. Through the synthesis and characterization of a library of ITI photoswitches, we discovered variants with a substantially increased thermal stability, reaching half-lives of up to 0.2 seconds. Based on spectroscopic and computational analyses, we demonstrate how different substituent positions on the ITI molecule can be used to tune its photophysical properties independently to fit the desired application. Additionally, the unique reactivity of the ITI derivative that featured a perfluoro-aromatic ring and had the most long-lived metastable state was shown to be useful for labeling of nucleophilic functional groups. The present research thus paves the way for using ITI photoswitches in photopharmacology and chemical biology., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The light-induced photocycloaddition of 9,10-phenanthrenequinone (PQ) with electron-rich alkenes (ERA), known as the PQ-ERA reaction, is a highly attractive photoclick reaction characterized by its operational simplicity and high biocompatibility. One essential aspect of photoclick reactions is their high rate, however the limited solubility of PQs often requires the use of a co-solvent. Evaluating the effect of different co-solvents on the PQ-ERA reaction and their influence on the reaction rate, we discovered that sulfur-containing compounds, in particular the frequently used solubilizing co-solvent DMSO, quench the triplet state of the PQ. These experimental results, supported by nanosecond-microsecond and ultrafast transient absorption data, show that even minimal amounts of DMSO result in a decreased lifetime of the reactive triplet state, essential for the photoclick reaction. Without DMSO as co-solvent, exceptionally high photoreaction quantum yields ( Φ P up to 93% with only 1 equivalent ERA) and complete conversion in seconds can be achieved. With these outstanding efficiencies, the PQ-ERA reaction can be used without excess ERA and at low light intensities, facilitating photoclick transformations in various future applications., Competing Interests: There are no competing conflicts of interests to declare., (This journal is © The Royal Society of Chemistry.)

Photocleavable protecting groups (PPGs) enable the precise spatiotemporal control over the release of a payload of interest, in particular a bioactive substance, through light irradiation. A crucial parameter that determines the practical applicability of PPGs is the efficiency of payload release, largely governed by the quantum yield of photolysis (QY). Understanding which parameters determine the QY will prove crucial for engineering improved PPGs and their effective future applications, especially in the emerging field of photopharmacology. The Contact Ion Pair (CIP) has been recognized as an important intermediate in the uncaging process, but the key influence of its fate on the quantum yield has not been explored yet, limiting our ability to design improved PPGs. Here, we demonstrate that the CIP escape mechanism of PPGs is crucial for determining their payload- and solvent-dependent photolysis QY, and illustrate that an intramolecular type of CIP escape is superior over diffusion-dependent CIP escape. Furthermore, we report a strong correlation of the photolysis QY of a range of coumarin PPGs with the DFT-calculated height of all three energy barriers involved in the photolysis reaction, despite the vastly different mechanisms of CIP escape that these PPGs exhibit. Using the insights obtained through our analysis, we were able to predict the photolysis QY of a newly designed PPG with particularly high accuracy. The level of understanding of the factors determining the QY of PPGs presented here will move the ever-expanding field of PPG applications forward and provides a blueprint for the development of PPGs with QYs that are independent of payload-topology and solvent polarity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The light-induced photocycloaddition of 9,10-phenanthrenequinone (PQ) with electron-rich alkenes (ERA), known as the PQ-ERA reaction, is a highly attractive photoclick reaction characterized by high selectivity, external non-invasive control with light and biocompatibility. The conventionally used PQ compounds show limited reactivity, which hinders the overall efficiency of the PQ-ERA reaction. To address this issue, we present in this study a simple strategy to boost the reactivity of the PQ triplet state to further enhance the efficiency of the PQ-ERA reaction, enabled by thiophene substitution at the 3-position of the PQ scaffold. Our investigations show that this substitution pattern significantly increases the population of the reactive triplet state ( 3 ππ*) during excitation of 3-thiophene PQs. This results in a superb photoreaction quantum yield ( Φ P , up to 98%), high second order rate constants ( k 2 , up to 1974 M -1 s -1 ), and notable oxygen tolerance for the PQ-ERA reaction system. These results have been supported by both experimental transient absorption data and theoretical calculations, providing further evidence for the effectiveness of this strategy, and offering fine prospects for fast and efficient photoclick transformations., Competing Interests: There are no competing conflicts of interests to declare., (This journal is © The Royal Society of Chemistry.)

Short, complementary DNA single strands with mismatched base pairs cannot undergo spontaneous formation of duplex DNA (dsDNA). Mismatch binding ligands (MBLs) can compensate this effect, inducing the formation of the double helix and thereby acting as a molecular glue. Here, we present the rational design of photoswitchable MBLs that allow for reversible dsDNA assembly by light. Careful choice of the azobenzene core structure results in excellent band separation of the E and Z isomers of the involved chromophores. This effect allows for efficient use of light as an external control element for duplex DNA formation and for an in-depth study of the DNA-ligand interaction by UV-Vis, SPR, and CD spectroscopy, revealing a tight mutual interaction and complementarity between the photoswitchable ligand and the mismatched DNA. We also show that the configuration of the switch reversibly dictates the conformation of the DNA strands, while the dsDNA serves as a chiral clamp and translates its chiral information onto the ligand inducing a preference in helical chirality of the Z isomer of the MBLs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Multi-responsive functional molecules are key for obtaining user-defined control of the properties and functions of chemical and biological systems. In this respect, pH-responsive photochromes, whose switching can be directed with light and acid-base equilibria, have emerged as highly attractive molecular units. The challenge in their design comes from the need to accommodate application-defined boundary conditions for both light- and protonation-responsivity. Here we combine time-resolved spectroscopic studies, on time scales ranging from femtoseconds to seconds, with density functional theory (DFT) calculations to elucidate and apply the acidochromism of a recently designed iminothioindoxyl (ITI) photoswitch. We show that protonation of the thermally stable Z isomer leads to a strong batochromically-shifted absorption band, allowing for fast isomerization to the metastable E isomer with light in the 500-600 nm region. Theoretical studies of the reaction mechanism reveal the crucial role of the acid-base equilibrium which controls the populations of the protonated and neutral forms of the E isomer. Since the former is thermally stable, while the latter re-isomerizes on a millisecond time scale, we are able to modulate the half-life of ITIs over three orders of magnitude by shifting this equilibrium. Finally, stable bidirectional switching of protonated ITI with green and red light is demonstrated with a half-life in the range of tens of seconds. Altogether, we designed a new type of multi-responsive molecular switch in which protonation red-shifts the activation wavelength by over 100 nm and enables efficient tuning of the half-life in the millisecond-second range., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The external photocontrol over peptide folding, by the incorporation of molecular photoswitches into their structure, provides a powerful tool to study biological processes. However, it is limited so far to switches that exhibit only a rather limited geometrical change upon photoisomerization and that show thermal instability of the photoisomer. Here we describe the use of an overcrowded alkene photoswitch to control a model β-hairpin peptide. This photoresponsive unit undergoes a large conformational change and has two thermally stable isomers which has major influence on the secondary structure and the aggregation of the peptide, permitting the phototriggered formation of amyloid-like fibrils.