Bidirectional Photoswitching of a Tailored Azobenzene with Red and Far‐Red Light Involving Triplet Sensitization in an Aqueous System

ABSTRACT Shifting action spectrum of azobenzene‐based photopharmaceuticals toward bio‐optical window is highly desired, since red/far‐red light offers improved tissue penetration and reduced cellular toxicity. While unidirectional photoswitching ( trans‐to‐cis and cis‐to‐trans ) of azobenzenes (AZO) with red/far‐red light is known in separate systems, achieving bidirectional photoswitching in a single system faces issues of spectral overlaps. Here, bidirectional photoswitching of a tailored azobenzene is achieved in a single bio‐relevant solution with red and far‐red light excitation. A new azobenzene molecule ( AZO‐N ) bearing four ortho ‐methoxy, and one para ‐N donor lipophile is synthesized. The AZO‐N exhibits separate n‐π* absorption bands and triplet energies for trans and cis isomers. As a result, trans ‐to‐ cis photoswitching is observed upon 625 nm excitation at the tail of the red‐shifted n‐π*absorption band via direct absorption, whereas cis ‐to‐ trans photoswitching is enabled upon 730 nm excitation through triplet sensitization. Further, triplet sensitization of AZO ‐based molecules could lead to singlet oxygen generation—experiments in the presence of serum albumin and glutathione (biological oxidative stress addressors), suggest no effect of singlet oxygen on the triplet‐sensitization of cis ‐ AZO‐N, and non‐significant change in the fingerprint all‐ α secondary structure of serum albumin. This advance presents modular design principles to develop practically functional azo‐based photopharmaceuticals.