Computational Rational Design of Bridgehead Nitrogen Heterocyclic Azobenzene Photoswitches.

Azobenzenes are proven to be one of the most successful molecular photoswitches applied across different fields such as organic chemistry, material science, cosmetics, and pharmaceuticals. Such a widespread implementation is possible because of their photochromic properties contingent upon the substitution pattern and aryl-core nature. In recent endeavors of molecular design, replacing one or both phenyl rings with heteroaromatics turned out to be a good strategy to access compounds with improved photoswitching properties, as well as to expand molecular diversity. One of the challenges related to the design of new azobenzene photoswitches is that it often includes the synthesis of large libraries of compounds due to limited methods for prediction of their properties. Herein, we present a computationally driven workflow for the design and synthesis of a novel class of azobenzene photoswitches, heteroaryl azobenzenes with N-bridgehead heterocycles─pyrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine. A small library of heteroaryl photoswitches was synthesized, and their photochemical properties were evaluated. Subsequently, these results were used to validate a computational approach, which included the in silico evaluation of a large library of designed photoswitch candidates leading to the synthesis of a new photoswitch with improved spectral properties, red-shifted λmax values.

• Publication year

  2025

• Venue

  Journal of Organic Chemistry

• Publication date

  2025-05-15

• Fields of study

  Medicine, Materials Science, Chemistry

• Identifiers
  DOI 10.1021/acs.joc.5c00731PMID 40371946
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Visible-Light-Activated Heteroaryl Azoswitches: Toward a More Colorful Future.

  2024cited by this paper
• Solar Azo-Switches for Effective E→Z Photoisomerization by Sunlight.

  2024cited by this paper
• Bis-azopyrazole Photoswitches for Efficient Solar Light Harvesting.

  2024cited by this paper
• Rational Design in Photopharmacology with Molecular Photoswitches.

  2023cited by this paper
• Pyrazolo - Pyrimidines as Targeted Anticancer Scaffolds - A Comprehensive Review.

  2023cited by this paper
• Recent Synthetic and Biological Developments on 1,2,4‐Triazolopyrimidines

  2023cited by this paper
• Photoisomerization of 2-Arylazoimidazoles under Visible Light: Identifying a Predictive Tool to Anticipate and Tune Likely Photoswitching Performance and Cis Half-Life.

  2023cited by this paper
• Light Switchable Metal Complexes: Introducing Photoresponsive Behaviour Through Azoheteroarenes

  2023cited by this paper
• Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells.

  2023cited by this paper
• Thiazolylazopyrazoles as Nonsymmetric Bis-Heteroaryl Azo Switches: High-Yield Visible-Light Photoisomerization and Increased Z-Isomer Stability by o-Carbonylation.

  2023cited by this paper
• Triazole-fused pyrimidines in target-based anticancer drug discovery.

  2023cited by this paper
• New tricks and emerging applications from contemporary azobenzene research

  2022cited by this paper
• On the Computational Design of Azobenzene-Based Multi-State Photoswitches

  2022cited by this paper
• Fast relaxing red and near-IR switchable azobenzenes with chalcogen and halogen substituents: periodic trends, tuneable thermal half-lives and chalcogen bonding

  2022cited by this paper
• Molecular Modeling Based on Time-Dependent Density Functional Theory (TD-DFT) Applied to the UV-Vis Spectra of Natural Compounds

  2022cited by this paper
• Visible‐light‐switchable azobenzenes: Molecular design, supramolecular systems, and applications

  2022cited by this paper
• Practical Ferrioxalate Actinometry for the Determination of Photon Fluxes in Production-Oriented Photoflow Reactors

  2022cited by this paper
• Design and Synthesis of Visible-Light-Responsive Azobenzene Building Blocks for Chemical Biology

  2022cited by this paper
• Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold.

  2022cited by this paper
• Best‐Practice DFT Protocols for Basic Molecular Computational Chemistry

  2022cited by this paper
• Synthesis, characterization, DFT, and TD-DFT studies of (E)-5-((4,6-dichloro-1,3,5-triazin-2-yl)amino)-4-hydroxy-3-(phenyldiazenyl)naphthalene-2,7-diylbis(hydrogen sulfite)

  2021cited by this paper
• Experimental and DFT study of UV–vis absorption spectra of azobenzene containing ester groups

  2021cited by this paper
• Advances and opportunities in the exciting world of azobenzenes

  2021cited by this paper
• Photoswitching of Diazocines in Aqueous Media.

  2021cited by this paper
• Azobispyrazole family as photoswitches combining (near-) quantitative bidirectional isomerization and widely tunable thermal half-lives from hours to years.

  2021cited by this paper
• Using Theory To Extend the Scope of Azobenzene Drugs in Chemotherapy: Novel Combinations for a Specific Delivery

  2021cited by this paper
• Molecular photoswitches in aqueous environments

  2021cited by this paper
• Access to azolopyrimidine-6,7-diamines as a valuable “building-blocks” to develop new fused heteroaromatic systems

  2021cited by this paper
• Structure–Activity Relationships of Pyrazolo[1,5-a]pyrimidin-7(4H)-ones as Antitubercular Agents

  2021cited by this paper
• Using azobenzene photocontrol to set proteins in motion

  2021cited by this paper
• Triazolopyrimidine Nuclei: Privileged Scaffolds for Developing Antiviral Agents with a Proper Pharmacokinetic Profile.

  2021cited by this paper
• Advances in Application of Azobenzene as a Trigger in Biomedicine: Molecular Design and Spontaneous Assembly

  2021cited by this paper
• Computational Design and Synthesis of a Deeply Red-Shifted and Bistable Azobenzene

  2020cited by this paper
• Dual Emission: Classes, Mechanisms and Conditions.

  2020cited by this paper
• Enlightening Materials with Photoswitches

  2020cited by this paper
• Photoswitchable CENP-E inhibitor enabling the dynamic control of chromosome movement and mitotic progression.

  2020cited by this paper
• Pyrazolo[1,5-a]pyrimidines-based fluorophores: a comprehensive theoretical-experimental study

  2020cited by this paper
• TD-DFT Prediction of the Intermolecular Charge-Transfer UV-Vis Spectra of Viologen Salts in Solution

  2020cited by this paper
• Competitive routes to cyclizations of polyfluoroalkyl-containing 2-tolylhydrazinylidene-1,3-diketones with 3-aminopyrazoles into bioactive pyrazoloazines

  2020cited by this paper
• Prescribed drugs containing nitrogen heterocycles: an overview

  2020cited by this paper
• General Principles for the Design of Visible‐Light‐Responsive Photoswitches: Tetra‐ortho‐Chloro‐Azobenzenes

  2020cited by this paper
• Applications of Photoswitches in the Storage of Solar Energy

  2019cited by this paper
• Recent Implementations of Molecular Photoswitches into Smart Materials and Biological Systems.

  2019cited by this paper
• 1,2,4-Triazolo[1,5-a]pyrimidines in drug design.

  2019cited by this paper
• Substituent Effects on 3-Arylazoindole Photoswitches.

  2019cited by this paper
• Heteroaryl azo dyes as molecular photoswitches

  2019cited by this paper
• Pyrazolo[1,5-a]pyrimidines: A Close Look into their Synthesis and Applications

  2019cited by this paper
• Designing Molecular Photoswitches for Soft Materials Applications

  2019cited by this paper
• Arylazo-3,5-dimethylisoxazoles - Azoheteroarene photoswitches exhibiting high Z-isomer stability, solid state photochromism and reversible light-induced phase transition.

  2019cited by this paper
• Effects of π-extension on pyrrole hemithioindigo photoswitches

  2019cited by this paper
• A combinatorial approach to improving the performance of azoarene photoswitches

  2019cited by this paper
• Evaluation of Substituent Effect in Z-Isomer Stability of Arylazo-1 H-3,5-dimethylpyrazoles: Interplay of Steric, Electronic Effects and Hydrogen Bonding.

  2018cited by this paper
• Photoswitching Behavior of 5-Phenylazopyrimidines: In Situ Irradiation NMR and Optical Spectroscopy Combined with Theoretical Methods.

  2018cited by this paper
• Azobenzene-based solar thermal fuels: design, properties, and applications.

  2018cited by this paper
• In Vivo Photopharmacology.

  2018cited by this paper
• Molecular Photoswitching Aided by Excited-State Aromaticity.

  2018cited by this paper
• Tyrosine kinase inhibition effects of novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines ligand: Synthesis, biological screening and molecular modeling studies.

  2018cited by this paper
• Theoretical study on the reaction mechanism of the thermal cis–trans isomerization of fluorine-substituted azobenzene derivatives

  2018cited by this paper
• A versatile method for the determination of photochemical quantum yields via online UV-Vis spectroscopy

  2018cited by this paper
• Photoswitchable double bonds: Synthetic strategies for tunability and versatility

  2018cited by this paper
• Tuning Azoheteroarene Photoswitch Performance through Heteroaryl Design.

  2017cited by this paper
• Photoswitchable molecules as key ingredients to drive systems away from the global thermodynamic minimum.

  2017cited by this paper
• Determining the Photoisomerization Quantum Yield of Photoswitchable Molecules in Solution and in the Solid State

  2017cited by this paper
• An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold.

  2017cited by this paper
• Making waves in a photoactive polymer film

  2017cited by this paper
• Direct and Versatile Synthesis of Red-Shifted Azobenzenes.

  2016cited by this paper
• Synthesis of Redshifted Azobenzene Photoswitches by Late-Stage Functionalization.

  2016cited by this paper
• A roadmap to success in photopharmacology.

  2015cited by this paper
• Red-Shifting Azobenzene Photoswitches for in Vivo Use.

  2015cited by this paper
• Visible-Light-Activated Molecular Switches.

  2015cited by this paper
• ortho-Fluoroazobenzenes: visible light switches with very long-Lived Z isomers.

  2014cited by this paper
• Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: discovery of novel [1,2,4]Triazolo[1,5-a]pyrimidines using a structure-guided core-refining approach.

  2014cited by this paper
• Arylazopyrazoles: azoheteroarene photoswitches offering quantitative isomerization and long thermal half-lives.

  2014cited by this paper
• A fast, visible-light-sensitive azobenzene for bioorthogonal ligation.

  2014cited by this paper
• Remote-controlling chemical reactions by light: towards chemistry with high spatio-temporal resolution.

  2014cited by this paper
• Photopharmacology: beyond proof of principle.

  2014cited by this paper
• Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals.

  2014cited by this paper
• Reversible photocontrol of biological systems by the incorporation of molecular photoswitches.

  2013cited by this paper
• The calculations of excited-state properties with Time-Dependent Density Functional Theory.

  2013cited by this paper
• Synthesis of Some Novel Arylazo Disperse Dyes Derived from 5‐Amino‐tetrazolo[1,5‐a]pyrimidin‐7‐ol as Coupling Component and Investigation of Their Absorption Spectra

  2013cited by this paper
• Photoswitching azo compounds in vivo with red light.

  2013cited by this paper
• o-Fluoroazobenzenes as readily synthesized photoswitches offering nearly quantitative two-way isomerization with visible light.

  2012cited by this paper
• Light-controlled tools.

  2012cited by this paper
• Photoswitching in azo dyes bearing thienylpyrrole and benzothiazole heterocyclic systems

  2012cited by this paper
• Photoisomerization in different classes of azobenzene.

  2012cited by this paper
• Azobenzene photoswitches for biomolecules.

  2011cited by this paper
• Azobenzene photoswitching without ultraviolet light.

  2011cited by this paper
• Single azopyridine-substituted porphyrin molecules for configurational and electronic switching.

  2010cited by this paper
• Switching single azopyridine supramolecules in ordered arrays on Au(111).

  2010cited by this paper
• The different photoisomerization efficiency of azobenzene in the lowest n pi* and pi pi* singlets: the role of a phantom state.

  2008cited by this paper
• Synthesis and solvatochromic properties of 3,6-bis-hetarylazo dyes derived from pyrazolo[1,5-a]pyrimidine

  2008cited by this paper
• The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals

  2008cited by this paper
• Extensive TD-DFT investigation of the first electronic transition in substituted azobenzenes

  2008cited by this paper
• Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections.

  2008cited by this paper
• A facile synthesis of some new pyrazolo[1,5-a]pyrimidine heterocyclic disazo dyes and an evaluation of their solvatochromic behaviour

  2007cited by this paper
• Pyrazolo[1,5-a]pyrimidines. Identification of the privileged structure and combinatorial synthesis of 3-(hetero)arylpyrazolo[1,5-a]pyrimidine-6-carboxamides.

  2007cited by this paper
• Studies with 2-(Arylhydrazono)aldehydes: Synthesis and Chemical Reactivity of Mesoxalaldehyde 2-Arylhydrazones and of Ethyl 2-Arylhydrazono-3-oxopropionates

  2007cited by this paper
• Synthesis of disazo pyrazolo [1,5 -a]pyrimidines

  2007cited by this paper
• Synthesis and solvatochromic properties of some disazo dyes derived from pyrazolo[1,5-a]pyrimidine derivatives

  2005cited by this paper
• Chemical actinometry (IUPAC Technical Report)

  2004cited by this paper

• No citing papers are available for this paper.