Tuning the Thermal Stability and Photoisomerization of Azoheteroarenes through Macrocycle Strain**

Abstract

Azobenzene and its derivatives are one of the most-widespread molecular scaffolds in a range of modern applications, as well as in fundamental research. After photoexcitation, azo-based photoswitches revert back to the most stable isomer in a timescale (t 1/2) that determines the range of potential applications. Attempts to bring t 1/2 to extreme values prompted to the development of azobenzene and azoheteroarene derivatives that either rebalance the E-and Z-isomer stabilities, or exploit unconventional thermal isomerization mechanisms. In the former case, one successful strategy has been the creation of macrocycle strain, which tends to impact the E/Z stability asymmetrically, and thus significantly modifies t 1/2. On the bright side, bridged derivatives have shown an improved optical switching owing to the higher quantum yields and absence of degradation. However, in most (if not all) cases, bridged derivatives display a reversed thermal stability (more stable Z-isomer), and smaller t 1/2 than the acyclic counterparts, which restricts their potential interest to applications requiring a fast forward and backwards switch. In this paper, we investigate the impact of alkyl bridges to the thermal stability of phenyl-azoheteroarenes using computational methods, and we reveal that is indeed possible to combine such improved photo-switching characteristics while preserving the regular thermal stability (more stable E-isomer), and increased t 1/2 values under the appropriate connectivity and bridge length. File list (2) download file view on ChemRxiv P3_Main.pdf (2.70 MiB) download file view on ChemRxiv P3_ESI.pdf (5.38 MiB)

Benchmarking of Density Functionals for Z-Azoarene Half-Lives via Automated Transition State Search

“…We excluded all azoarenes that featured extended alkyl chains, 87 transition metal complexes, 88,89 or macrocycles. [90][91][92] We decided not to include these classes of azoarenes because of the exponentially larger computational cost associated with evaluating the conformational space of alkyl chains and inconsistent performance of density functionals for organometallic species. 93,94…”

“…After searching the literature for experimental half-lives and corresponding k exp , we identified many more azoarenes than we could benchmark in a single report. We excluded all azoarenes that featured extended alkyl chains, transition-metal complexes, , or macrocycles. − We decided not to include these classes of azoarenes because of the exponentially larger computational cost associated with evaluating the conformational space of alkyl chains and the inconsistent performance of density functionals for organometallic species. , …”

Towards low-energy-light-driven bistable photoswitches: ortho-fluoroaminoazobenzenes

“…We also considered the rotational pathway for all selected molecules applying broken-symmetry UDFT. The rotational transition states (with the CNNC dihedral of about 90° and both CNN units bent) are expected to exhibit homolytic cleavage of the azo bond and, therefore, RDFT is expected to fail [70,71]. Interestingly, for the recently introduced azobispyrazole family mentioned above, the rotational barriers calculated with UDFT were found to be lower than the experimental ones, in contrast to the inversion barriers (see above) [68].…”

Photophosphatidylserine Guides Natural Killer Cell Photoimmunotherapy via Tim-3

“…Photoswitchable molecules are ideals to study biological systems, with broad applications, low toxicity, high spatiotemporal resolution, and convenient operability. − The configuration of bioactive molecules can be efficiently converted to each other via different wavelengths of light to reversibly alter their biological activity. Among multiple photoswitchable moieties, azobenzene is undoubtedly the most prominent scaffold for exploring photopharmacology elements in bioactive compounds with long-thermal stability of the cis state, , high-yield transformed ratio, rapid isomerization rate, and facile operation …”