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Azoarene photoswitches are versatile molecules that interconvert from their E-isomer to their Z-isomer with light. Azobenzene is a prototypical photoswitch but its derivatives can be poorly suited for in vivo applications such as photopharmacology due to undesired photochemical reactions promoted by ultraviolet light and the relatively short half-life (t1/2) of the Z-isomer (2 days). Experimental and computational studies suggest that these properties (λmax of the E isomer and t1/2 of the Z-isomer) are inversely related. We identified isomeric azobisthiophenes and azobisfurans from a high-throughput screening study of 1540 azoarenes as photoswitch candidates with improved λmax and t1/2 values relative to azobenzene. We used density functional theory to predict the activation free energies and vertical excitation energies of the E- and Z-isomers of 2,2- and 3,3-substituted azobisthiophenes and azobisfurans. The half-lives depend on whether the heterocycles are π-conjugated or cross-conjugated with the diazo π-bond. The 2,2-substituted azoarenes both have t1/2 values on the scale of 1 hour, while the 3,3-analogues have computed half-lives of 40 and 230 years (thiophene and furan, respectively). The 2,2-substituted heteroazoarenes have significantly higher λmax absorptions than their 3,3-substituted analogues: 76 nm for azofuran and 77 nm for azothiophene.
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Efficient discovery of visible light-activated azoarene photoswitches with long half-lives using active search
Photoswitches are molecules that undergo a reversible, structural isomerization after exposure to different wavelengths of light. The dynamic control offered by molecular photoswitches is favorable for applications in materials chemistry, photopharmacology, and catalysis. Ideal photoswitches absorb visible light and have long-lived metastable isomers. We used high throughput virtual screening to predict the absorption maxima (λmax) of the E-isomer and half-lives (t1/2) of the Z-isomer. However, computing the photophysical and kinetic properties of each entry of a virtual molecular library containing 103–106 entries with density functional theory is prohibitively time-consuming. We applied active search, a machine learning technique to intelligently search a chemical search space of 255991 photoswitches based on 29 known azoarenes and their derivatives. We iteratively trained the active search algorithm based on whether a candidate absorbed visible light (λmax > 450 nm). Active search was found to triple the discovery rate compared to random search. Further, we projected 1962 photoswitches to 2D using the Uniform Manifold Approximation and Projection (umap) algorithm and found that λmax depends on the core, which is tunable with substituents. We then incorporated a second stage of screening with to predict the stabilities of the Z-isomers for the top 1% of candidates. We identified four ideal photoswitches that concurrently satisfy λmax > 450 nm and t1/2 > 2 hours; the range of λmax and t1/2 range from 465 to 531 nm and hours to years, respectively.
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- Award ID(s):
- 1940224
- PAR ID:
- 10296606
- Date Published:
- Journal Name:
- ChemRxiv
- ISSN:
- 2573-2293
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.33774/chemrxiv-2021-w32rs
