Michael M. Lerch

Orthogonal photoswitching in a multifunctional molecular system.

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.

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.

Direct and Versatile Synthesis of Red‐Shifted Azobenzenes

A straightforward synthesis of azobenzenes with bathochromically-shifted absorption bands is presented. It employs an ortho-lithiation of aromatic substrates, followed by a coupling reaction with aryldiazonium salts. The products are obtained with good to excellent yields after simple purification. Moreover, with the presented methodology, a structurally diverse panel of different azobenzenes, including unsymmetric tetra-ortho-substituted ones, can be readily obtained, which paves the way for future development of red-light-addressable azobenzene derivatives for in vivo application.

Ciprofloxacin–Photoswitch Conjugates: A Facile Strategy for Photopharmacology

Photopharmacology aims to locally treat diseases and study biological processes with photoresponsive drugs. Herein, easy access to photoswitchable drugs is crucial, which is supported by simple and robust drug modifications. We investigated the possibility of creating drugs that can undergo remote activation and deactivation with light, by conjugating molecular photoswitches to the exterior of an existing drug in a single chemical step. This facile strategy allows the convenient introduction of various photochromic systems into a drug molecule, rendering it photoresponsive. To demonstrate the feasibility of this approach, two photoswitch-modified ciprofloxacin antibiotics were synthesized. Remarkably, for one of them a 50-fold increase in activity compared to the original ciprofloxacin was observed. Their antimicrobial activity could be spatiotemporally controlled with light, which was exemplified by bacterial patterning studies.

Rapid Access to β‐Trifluoromethyl‐Substituted Ketones: Harnessing Inductive Effects in Wacker‐Type Oxidations of Internal Alkenes

We present a practical trifluoromethyl-directed Wacker-type oxidation of internal alkenes that enables rapid access to β-trifluoromethyl-substituted ketones. Allylic trifluoromethyl-substituted alkenes bearing a wide range of functional groups can be oxidized in high yield and regioselectivity. The distance dependence of the regioselectivity was established by systematic variation of the number of methylene units between the double bond and the trifluoromethyl group. The regioselectivity enforced by traditional directing groups could even be reversed by introduction of a competing trifluoromethyl group. Besides being a new powerful synthetic method to prepare fluorinated molecules, this work directly probes the role of inductive effects on nucleopalladation events.

The (photo)chemistry of Stenhouse photoswitches: Guiding principles and system design

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.

Shedding Light on the Photoisomerization Pathway of Donor–Acceptor Stenhouse Adducts

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.

Tailoring Photoisomerization Pathways in Donor–Acceptor Stenhouse Adducts: The Role of the Hydroxy Group

Donor-acceptor Stenhouse adducts (DASAs) are a rapidly emerging class of visible light-activatable negative photochromes. They are closely related to (mero)cyanine dyes with the sole difference being a hydroxy group in the polyene chain. The presence or absence of the hydroxy group has far-reaching consequences for the photochemistry of the compound: cyanine dyes are widely used as fluorescent probes, whereas DASAs hold great promise for visible light-triggered photoswitching. Here we analyze the photophysical properties of a DASA lacking the hydroxy group. Ultrafast time-resolved pump-probe spectroscopy in both the visible and IR region show the occurrence of E-Z photoisomerization on a 20 ps time scale, similar to the photochemical behavior of DASAs, but on a slower time scale. In contrast to the parent DASA compounds, where the initial photoisomerization is constrained to a single position (next to the hydroxy group), 1H NMR in situ-irradiation studies at 213 K reveal that for nonhydroxy DASAs E-Z photoisomerization can take place at two different bonds, yielding two distinct isomers. These observations are supported by TD-DFT calculations, showing that in the excited state the hydroxy group (pre)selects the neighboring C2-C3 bond for isomerization. The TD-DFT analysis also explains the larger solvatochromic shift observed for the parent DASAs as compared to the nonhydroxy analogue, in terms of the dipole moment changes evoked upon excitation. Furthermore, computations provide helpful insights into the photoswitching energetics, indicating that without the hydroxy group the 4π-electrocyclization step is energetically forbidden. Our results establish the central role of the hydroxy group for DASA photoswitching and suggest that its introduction allows for tailoring photoisomerization pathways, presumably both through (steric) fixation via a hydrogen bond with the adjacent carbonyl group of the acceptor moiety, as well as through electronic effects on the polyene backbone. These insights are essential for the rational design of novel, improved DASA photoswitches and for a better understanding of the properties of both DASAs and cyanine dyes.

Solvent Effects on the Actinic Step of Donor–Acceptor Stenhouse Adduct Photoswitching

Abstract 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.

Wavelength-selective cleavage of photoprotecting groups

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.