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.

Center for Systems Chemistry Stratingh Institute for Chemistry University of Groningen Nijenborgh 7 Groningen The Netherlands

CNR ICCOM via Madonna del Piano 10 50019 Sesto Fiorentino Italy

Department of Medicinal Chemistry Photopharmacology and Imaging Groningen Research Institute of Pharmacy University of Groningen A Deusinglaan 1 9713 AV Groningen The Netherlands

Department of Radiology Medical Imaging Center University Medical Center Groningen Hanzeplein 1 9713GZ Groningen The Netherlands

Faculty of Natural Sciences Comenius University Ilkovičova 6 SK 842 15 Bratislava Slovak Republic

Faculty of Natural Sciences Department of Chemistry Matej Bel University Tajovského 40 SK 97400 Banská Bystrica Slovak Republic

Institute for Molecules and Materials FELIX Laboratory Radboud University Toernooiveld 7c 6525 ED Nijmegen The Netherlands

LENS European Laboratory for Non Linear Spectroscopy 50019 Sesto Fiorentino FI Italy

Nantes Université CNRS CEISAM UMR 6230 F 44000 Nantes France

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacky University Olomouc Křížkovského 511 8 77900 Olomouc Czech Republic

Van't Hoff Institute for Molecular Sciences University of Amsterdam Science Park 904 1098 XH Amsterdam The Netherlands

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