A Sustainable Improvement of ω-Bromoalkylphosphonates Synthesis to Access Novel KuQuinones

Owing to the attractiveness of organic phosphonic acids and esters in the pharmacological field and in the functionalization of conductive metal-oxides, the research of effective synthetic protocols is pivotal. Among the others, ω-bromoalkylphosphonates are gaining particular attention because they are useful building blocks for the tailored functionalization of complex organic molecules. Hence, in this work, the optimization of Michaelis–Arbuzov reaction conditions for ω-bromoalkylphosphonates has been performed, to improve process sustainability while maintaining good yields. Synthesized ω-bromoalkylphosphonates have been successfully adopted for the synthesis of new KuQuinone phosphonate esters and, by hydrolysis, phosphonic acid KuQuinone derivatives have been obtained for the first time. Considering the high affinity with metal-oxides, KuQuinones bearing phosphonic acid terminal groups are promising candidates for biomedical and photo(electro)chemical applications

3-morpholino-7-[N-methyl-N-(4′-carboxyphenyl)amino]phenothiazinium chloride

The synthesis of 3-morpholino-7-[N-methyl-N-(4′-carboxyphenyl)amino]phenothiazinium chloride is reported here. Interestingly, non-symmetric phenothiazinium salt is functionalized with a carboxylic acid group that allows the easy and stable anchoring on metal oxides. In addition, the morpholine unit reduces the dye aggregation tendency; thus, improving its potential applications in the biomedical and photo-electrocatalytic field

CT Perfusion as a Predictor of the Final Infarct Volume in Patients with Tandem Occlusion

Background: CT perfusion (CTP) is used in patients with anterior circulation acute ischemic stroke (AIS) for predicting the final infarct volume (FIV). Tandem occlusion (TO), involving both intracranial large vessels and the ipsilateral cervical internal carotid artery could generate hemodynamic changes altering perfusion parameters. Our aim is to evaluate the accuracy of CTP in the prediction of the FIV in TOs. Methods: consecutive patients with AIS due to middle cerebral artery occlusion, referred to a tertiary stroke center between March 2019 and January 2021, with an automated CTP and successful recanalization (mTICI = 2b - 3) after endovascular treatment were retrospectively included in the tandem group (TG) or in the control group (CG). Patients with parenchymal hematoma type 2, according to ECASS II classification of hemorrhagic transformations, were excluded in a secondary analysis. Demographic, clinical, radiological, time intervals, safety, and outcome measures were collected. Results: among 319 patients analyzed, a comparison between the TG (N = 22) and CG (n = 37) revealed similar cerebral blood flow (CBF) > 30% (29.50 +/- 32.33 vs. 15.76 +/- 20.93 p = 0.18) and FIV (54.67 +/- 65.73 vs. 55.14 +/- 64.64 p = 0.875). Predicted ischemic core (PIC) and FIV correlated in both TG (tau = 0.761, p < 0.001) and CG (tau = 0.315, p = 0.029). The Bland-Altmann plot showed agreement between PIC and FIV for both groups, mainly in the secondary analysis. Conclusion: automated CTP could represent a good predictor of FIV in patients with AIS due to TO

Catalytic and photocatalytic processes in sustainable small molecule activation

Small-molecule activation is a fundamental process for several organic transformations, where abundant, cheap and readily accessible molecules such as O2, N2, CO2, H2 and H2O2 are involved. Such molecules are usually kinetically inert and the research of appropriate catalysts or photocatalysts to activate them is widely active. Moreover, several studies concerning the development of new active molecules to construct artificial photosynthetic devices are in progress. In this framework, in our research group, few years ago a new class of quinoid compounds called KuQuinones (KuQ) has been synthesized. These compounds are characterized by a pentacyclic, planar and fully conjugated skeleton, which is responsible of their intense absorption in the visible region of the spectrum. Thanks to their quinoid structure, which derives from the condensation of two hydroxy-naphtoquinone units, KuQuinones can accept multiple electrons and their reduction potential for the generation of the radical anion (KuQ•-) is very low if compared with the same process in similar compounds. Such favourable properties were studied quite in detail, and Chapter 2 of this thesis is devoted to the application of KuQuinones as sensitizers in photoelectrochemical devices. In particular, among this class of devices our interest has been focused on the application of KuQuinones as photocatalyst in the light driven water oxidation process, which is considered a valid approach to achieve renewable energy production. To explore this field of application, KuQuinones have been firstly immobilized on an electrode surface, such as Indium-Tin Oxide (ITO). Afterwards, the photoinduced electron transfer process has been studied, using a simple model system where a mono-electronic electron donor molecule, such as triethanolamine or alternatively ascorbic acid, was used. In this context, good results have been achieved using an amphiphilic KuQuinone derivative, which has been deposited on ITO through Langmuir-Blodgett technique, obtaining organized and well packed mono- and multilayers on the electrode surface. Such modified electrodes showed good efficiencies in the photoinduced electron transfer process, in the presence of TEOA. In particular, upon irradiation of the electrode, one electron is promoted to the excited state, where KuQuinone is a strong oxidant and it can take an electron from the sacrificial electron donor species, thus forming the radical anion KuQ•-. Afterwards, a further electron transfer occurs toward the ITO surface, to close the circuit. These promising results prompted us to explore the use of KuQuinones as photocatalysts in the water splitting process. In principle, in the photoelectrochemical cell, once excited, KuQuinones can oxidize water through a multiple electrons process. In fact, KuQuinones can accept two electrons and for this reason H2O2 is the expected reaction product, coming from the 2-electrons oxidation of water. As a matter of fact, preliminary results showed that in our experimental conditions a significant photocurrent signal was detected, indicating that water oxidation occurred. Additionally, thanks to the promising results obtained in such photoelectrochemical devices, carboxylic acid-functionalized KuQuinones have been synthesized and used as sensitizers in ptype Dye Sensitized Solar Cells, using Nickel-Oxide as supporting electrode. Results highlighted that KuQuinones-sensitized cells showed better performance than Ery B, a conventional benchmark dye. Interestingly, despite the lack of electronic conjugation between the anchoring group and the light-absorbing unit, the photoinduced charge transfer occurred through space and not through the conjugated linker, as predictable. Finally, in order to better understand KuQuinones spectroscopic behaviour, a detailed investigation of possible equilibria in different solvents has been performed. Chapter 3 of the thesis will be focused on the development of photoelectrochemical devices for the oxygen activation. In this chapter it is demonstrated that photocatalysis resulted an efficient tool to activate dioxygen using a porphyrin sensitizer. In fact, in our research group over the last decade, the appealing properties of meso-tetraferrocenylporphyrins have been widely investigated. Such porphyrins are characterized by interesting electronic and electrochemical properties, hence, their application as photocatalyst for dioxygen reduction has been already studied. However, devices showed low efficiencies and the synthesis of the appropriate porphyrin derivative in some cases proceeded through laborious procedures. Therefore, Chapter 3 summarize the optimization of the photoelectrochemical cell in order to evaluate the best compromise among the feasibility of the synthetic procedure, the stability of the porphyrin layer on ITO and the optimal photoelectrochemical response toward the generation of the superoxide anion, which is one of the most reactive oxygen species. Finally, together with dioxygen, also hydrogen peroxide constitutes an efficient and sustainable oxidant. As for molecular oxygen, hydrogen peroxide is kinetically inert toward oxidation reactions so it must be activated. Chapter 4 will concern the application of a sustainable vanadium- based system for the synthesis of biologically active compounds. Specifically, reaction between H2O2 and commercially available vanadium catalyst precursors, leads to the generation of peroxido-V derivatives, which are very effective species for the oxidation of several organic and inorganic substrates. Among them, V-peroxocomplexes have been used to oxidize bromide ion to effective brominating species, thus mimicking the mechanisms of action of the Vdependent bromoperoxidase enzyme. This system allowed us to synthesize important brominated thymol derivatives. Among other properties, 4-bromothymol resulted a very effective antibacterial agent against important bacterial strains, which are responsible of dangerous infections for humans. These results open the opportunity to introduce 4-bromothymol as active ingredient in several industrial products in substitution of existing antibacterial agents

Easy to use DFT approach for computational pKa determination of carboxylic acids

In pKa computational determination, the challenge in exploring and fostering new methodologies and approaches goes in parallel with the amelioration of computational performances. In this paper a "ready to use methodology" has been compared to other strategies, such as the re-shaping in solvation cavity (Bondi radius re-shaping), wanting to assess its reliability in predicting the pKa of a broad list of carboxylic acids. Thus, the functionals B3LYP and CAM-B3LYP have been selected, using SMD as continuum solvation model. Exploiting our previous results, two water molecules were made explicit on the reaction centre. Data show that our model (CAM-B3LYP/2H2 O) is capable to accurately predict pKa, leading to mean absolute error (MAE) values lower than 0.5. Noteworthy, good results were achieved in computing the pKa of substituents bearing nitro and cyano groups. Focusing on B3LYP, eventually remarkable outputs were obtained only when Bondi correction was applied to the complex with two water molecules. Hence, massive outcomes were obtained in foreseeing the trichloro and trifluoro acetic acid pKa. These findings demonstrated that no complex level of theory nor external factor is required to accurately predict carboxylic acids pKa, with MAE well below 0.5 units

The Beneficial Sinergy of MW Irradiation and Ionic Liquids in Catalysis of Organic Reactions

The quest for sustainable processes is becoming more and more important, with catalysis playing a major role in improving atom economy and reducing waste. Organic syntheses with less need of protecting/de-protecting steps are highly desirable. The combination of microwave irradiation, as energy source, with ionic liquids, as both solvents and catalysts, offered interesting solutions in recent years. The literature data of the last 15 years concerning selected reactions are presented, highlighting the importance of microwave (MW) technology coupled with ionic liquids

Synthesis of soluble quinacridone photocatalysts for the homogeneous oxidation of thioethers

Evaluation of quinacridone (QA) derivatives as homogeneous metal-free photocatalysts is here presented. QA derivatives were synthetized and systematically characterized, measuring their ground state and excited state redox potentials in dichloromethane (DCM) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), in order to understand how structural modifications influenced their photocatalytic properties. In particular, the effect of dicyanomethylene and nitro EWG groups was investigated, in order to develop a photocatalyst capable of promoting oxidative processes in the presence of molecular oxygen. Among the analyzed derivatives, 2,9-dinitro-N,N & PRIME;-dibutylquinacridone (DNDBQA) was the one with the highest excited state reduction potential (E-red*=1.60 V in HFIP vs SCE), while N,N'-dibutylquinacridone (DBQA) showed valuable excited state redox potentials (E-red*=1.29 V; E-ox*=-1.28 V in HFIP vs SCE), making it suitable for bimodal applications in oxidative and reductive photocatalytic processes. Afterwards, the synthetized QA derivatives were examined as photocatalysts to promote the selective aerobic oxidation of thioether to sulfoxide. Promising results in thioanisole oxidation were achieved with all the QA derivatives tested as photocatalysts, in terms of yield and selectivity. Remarkably, DBQA showed the best performances, catalyzing the reaction in only 20 minutes, using 0.5 % of the photocatalyst, and showing excellent performances in the oxidation of several thioether derivatives

Photocatalyzed Oxygenation Reactions with Organic Dyes: State of the Art and Future Perspectives

Oxygen atom incorporation into organic molecules is one of the most powerful strategies to increase their pharmacological activity and to obtain valuable intermediates in organic synthesis. Traditional oxidizing agents perform very well, but their environmental impact and their low selectivity constitute significant limitations. On the contrary, visible-light-promoted oxygenations represent a sustainable method for oxidizing organic compounds, since only molecular oxygen and a photocatalyst are required. Therefore, photocatalytic oxygenation reactions exhibit very high atom-economy and eco-compatibility. This mini-review collects and analyzes the most recent literature on organo-photocatalysis applications to promote the selective oxygenation of organic substrates. In particular, acridinium salts, Eosin Y, Rose Bengal, cyano-arenes, flavinium salts, and quinone-based dyes are widely used as photocatalysts in several organic transformations as the oxygenations of alkanes, alkenes, alkynes, aromatic compounds, amines, phosphines, silanes, and thioethers. In this context, organo-photocatalysts proved to be highly efficient in catalytic terms, showing similar or even superior performances with respect to their metal-based counterparts, while maintaining a low environmental impact. In addition, given the mild reaction conditions, visible-light-promoted photo-oxygenation processes often display remarkable selectivity, which is a striking feature for the late-stage functionalization of complex organic molecules

Lignosulfonate Microcapsules for Delivery and Controlled Release of Thymol and Derivatives

Thymol and the corresponding brominated derivatives constitute important biological active molecules as antibacterial, antioxidant, antifungal, and antiparasitic agents. However, their application is often limited, because their pronounced fragrance, their poor solubility in water, and their high volatility. The encapsulation of different thymol derivatives into biocompatible lignin-microcapsules is presented as a synergy-delivering remedy. The adoption of lignosulfonate as an encapsulating material possessing relevant antioxidant activity, as well as general biocompatibility allows for the development of new materials that are suitable for the application in various fields, especially cosmesis. To this purpose, lignin microcapsules containing thymol, 4-bromothymol, 2,4-dibromothymol, and the corresponding O-methylated derivatives have been efficiently prepared through a sustainable ultrasonication procedure. Actives could be efficiently encapsulated with efficiencies of up to 50%. To evaluate the applicability of such systems for topical purposes, controlled release experiments have been performed in acetate buffer at pH 5.4, to simulate skin pH: all of the capsules show a slow release of actives, which is strongly determined by their inherent lipophilicity