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Towards Highly-Efficient Two-Photon Absorbing Sensitizers within a Confined Chromophore Space: From Computer-Aided Design to New Concepts and Applications

Periodic Reporting for period 1 - TWOSENS (Towards Highly-Efficient Two-Photon Absorbing Sensitizers within a Confined Chromophore Space:From Computer-Aided Design to New Concepts and Applications)

Reporting period: 2018-01-01 to 2019-12-31

Materials exhibiting large two-photon absorption (TPA) are highly required to fully exploit the potential of modern laser technologies in microfabrication, high-capacity data storage as well as in biomedical applications, such as photodynamic cancer therapy and high-resolution 3D bioimaging. All these techniques take advantage of the TPA process, which refers to a simultaneous absorption of two photons of half the nominal excitation energy by a single molecule. This allows for (a) the excitation of molecules by low-energy near-IR light in the so-called biological transparency window (650-1000 nm), beneficial in a deeper tissue/material penetration and reduced photodamage as compared to one-photon absorption in the UV region, and (b) more control and higher spatial resolution via quadratic dependence of the TPA rate on the intensity of the incident laser beam. However, most of sensitizers currently used in clinic or technological applications is poorly compatible with two-photon excitation due to their low TPA cross-sections (often much smaller than 100 GM), that requires very high light doses and may lead to undesired damages of essential biological structures or material.

Most design strategies to enhance TPA cross-sections rely on construction of extremely large π-conjugated molecules or aggregates, which are not appreciated in practice due to difficulties connected with their expensive synthesis, limited solubility in polar media and/or low cell permeability. All these drawbacks hamper the use of large π-conjugated dyes in real applications and more sophisticated and smaller systems featuring a high photochemical stability along with their efficient, eco-friendly and low-cost synthesis, are thus needed.

The primary aim of this action was to provide material chemists with useful structure-property relationships and rational design (computed-aided screening) of novel heteroaromatic-based sensitizers displaying very high TPA cross-sections (> 1000 GM) within a confined chromophore space, with a particular focus on thiazole-annulated heteroaromatics due to their excellent photochemical and thermal stabilities and possibility of their further ease functionalization. In addition, we also aimed at optimizing synthetic pathways, reaction conditions, catalysts and transformations of specific functional groups leading to valuable building blocks, which were applied in the synthesis of target TPA dyes.
The main objective of this action was to design novel heteroaromatic building blocks, which would allow to enhance TPA activity of given chromophores in the near-infrared (NIR) spectral region. This was achieved by using state-of-the-art quantum-chemical calculations of NLO properties for a large series of structurally diverse heteroaromatic systems. A systematic computer-aided modelling, focused primarily on calculations of TPA cross-sections, allowed us to avoid trial-and-error experimentation and to target at a set of highly efficient TPA dyes using various S,N-heteroarene platforms and substitution patterns.

In this regard, we found out that our concept of regioisomeric control of NLO properties proposed originally for a benzothiazole ring is valid generally and can be applied to a wide range of heteroaromatic scaffolds. This strategy (an appropriate arrangement of electron-donating/withdrawing substituents on the heteroaromatic core while keeping the molecular weight constant) offers thus an elegant way to maximize TPA activity within a confined chromophore space – the more so the larger is the “asymmetry” between two positions of the heteroaromatic scaffold considered for connection of donor and acceptor substituents. In addition, we also discovered, that this concept can be applied to centrosymmetric (quadrupolar) dyes with electron-rich and/or electron-defficient centres.

The most promising candidates identified by quantum-chemical calculations were synthesized in our laboratory and are currently under intensive photophysical characterizations, including steady UV-vis absorption/emission spectroscopy as well as laser measurements of TPA cross-sections in collaboration with our partners.

In the next stage, we developed efficient synthetic strategies for specific functional group transformations (one-pot reductive methylation of nitrobenzazoles, direct halogenations of deactived heteroaromatics, oxidative homocoupling of donor-substituted benzazoles etc.) and refined proposed mechanisms of some reactions, both facilitating the preparation of valuable building blocks and target TPA dyes. When attempting to prepare a reactive Pd species suitable for cross-coupling reactions, we characterized an unprecedented Pd7 nanocluster, whose electronic structure and aromatic character are attractive for a wide range of applications, including quantum computing or imaging.

The first samples were also subjected to two-photon excited fluorescence (TPEF) microscopy, showing application potential of our dyes in bioimaging, namely by mapping the atherosclerosis reflected in aorta size and changes in its structure. The good TPA response along with possibility to combine TPEF images with second-harmonic generation (SHG) microscopy for non-centrosymmetric push-pull dyes allows for higher spatial resolution than obtained solely by TPEF. This can lead to better understanding the plaque formation and mechanisms behind aorta narrowing using non-invasive NLO techniques and can be thus indirectly helpful in finding appropriate medication (note that vascular circulatory diseases are responsible for 35 % of all death each year and are related to hardening and narrowing of the aorta). To increase the selectivity of our TPA dyes to bind specifically to certain organelles or biomolecules, further modification of the pendant groups is required and it is ongoing in our laboratories.

In addition, we have shown that readily available 4,7-bis(arylethynyl)heteroarenes end-capped with NO2 groups display apart from large TPA activity also high quantum yields of excited triplet-state and singlet oxygen generation (50-70%). This along with their absorption/emission properties makes these dyes attractive as efficient metal-free photosensitisers in the photodynamic therapy (PDT) using both blue light irradiation (preferred in the treatment of skin cancer) and red light laser utilizing nonlinear two-photon excitation (PDT treatment, where a deep tissue penetration is required).

Completed works related to this action have been published in 7 peer-reviewed papers and another 5 manuscripts are expected to be submitted within next 12 months.
Although this action is in the end, the research related to it is ongoing further. We plan to exploit the application potential of all herein prepared TPA sensitizers, with a particular emphasis on TPEF microscopy and singlet oxygen generation.

Overall, this action allowed the fellow to relocate from abroad to his home country and to integrate smoothly into a top-level national research institution. Besides, it boosted his career towards being independent research group leader, strengthened the collaboration with specialists in laser spectroscopy and allowed him to secure long-term funding from national R&D agency, so the fellow and his team can continuously work on projects related to this action – specifically, development of highly efficient sensitizers for nonlinear optics and solar cell devices.