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.

New Insights in the Computational pKb Determination of Primary Amines and Anilines.

Extensive research has already provided reliable methods for the in silico prediction of pKa, while a trustworthy strategy for pKb determination is still being sought. Indeed, the approaches previously exploited for computing pKa have shown their weakness in predicting pKb. In the light of the exceptional reliability demonstrated in the pKa calculation of a wide panel of organic acids, in this work, we exploited our "easy to use methodology", based on the direct approach, to predict the pKb of primary amines. Herein, CAM-B3LYP was compared to WB97XD and B3PW91, exploring the solvation model based on density (SMD) and the polarizable continuum model (PCM), in the presence of two explicit water molecules. Noteworthy, CAM-B3LYP and WB97XD returned completely different solvent accessible surfaces (SAS) and electron potential maps (EPM) for the bases and the conjugated acids, independently from the nature of the substituents. Once again, CAM-B3LYP/SMD/2H2O method confirmed its remarkable reliability, leading to a minimum average error (MAE) lower than 0.3. This outstanding result strengthens the trustworthiness of our method, already successfully applied to predict the pKa of different substituted phenols and carboxylic acids. Thus, our "easy-to-use" process can predict also the pKb of primary ammines and anilines, always ensuring consistent outputs.

Towards the "Eldorado" of pKa Determination: A Reliable and Rapid DFT Model.

The selection of a "perfect tool" for the theoretical determination of acid-base dissociation constants (Ka) is still puzzling. Recently, we developed a user-friendly model exploiting CAM-B3LYP for determining pKa with impressive reliability. Herein, a new challenge is faced, examining a panel of functionals belonging to different rungs of the "Jacob's ladder" organization, which classifies functionals according to their level of theory. Specifically, meta-generalized gradient approximations (GGAs), hybrid-GGAs, and the more complex range-separated hybrid (RSH)-GGAs were investigated in predicting the pKa of differently substituted carboxylic acids. Therefore, CAM-B3LYP, WB97XD, B3PW91, PBE1PBE, PBEPBE and TPSSTPSS were used, with 6-311G+(d,p) as the basis set and the solvation model based on density (SMD). CAM-B3LYP showed the lowest mean absolute error value (MAE = 0.23) with relatively high processing time. PBE1PBE and B3PW91 provided satisfactory predictions (MAE = 0.34 and 0.38, respectively) with moderate computational time cost, while PBEPBE, TPSSTPSS and WB97XD led to unreliable results (MAE > 1). These findings validate the reliability of our model in predicting carboxylic acids pKa, with MAE well below 0.5 units, using a simplistic theoretical level and a low-cost computational approach.

KuQuinone as a Highly Stable and Reusable Organic Photocatalyst in Selective Oxidation of Thioethers to Sulfoxides.

A chemoselective photocatalytic system to perform thioether oxidation to sulfoxide is presented. The light-induced oxidation process is here promoted by a metal-free quinoid catalyst, namely 1-hexylKuQuinone (KuQ). Reactions performed in a fluorinated solvent (i.e., HFIP), using O2 as the oxidant, at room temperature, lead to complete thioanisole conversion to methyl phenyl sulfoxide in 60 min. Remarkably, the system can be recharged and recycled without a loss of activity and selectivity, reaching turnover numbers (TONs) higher than 4000. Excellent catalytic performances and full selectivity have also been obtained for the photocatalytic oxidation of substituted thioanisole derivatives, aliphatic, cyclic, and diaryl thioethers. Likewise, the oxidation of heteroaromatic organosulfur compounds can be accomplished, with longer reaction times.

An Accurate Approach for Computational pKa Determination of Phenolic Compounds.

Computational chemistry is a valuable tool, as it allows for in silico prediction of key parameters of novel compounds, such as pKa. In the framework of computational pKa determination, the literature offers several approaches based on different level of theories, functionals and continuum solvation models. However, correction factors are often used to provide reliable models that adequately predict pKa. In this work, an accurate protocol based on a direct approach is proposed for computing phenols pKa. Importantly, this methodology does not require the use of correction factors or mathematical fitting, making it highly practical, easy to use and fast. Above all, DFT calculations performed in the presence two explicit water molecules using CAM-B3LYP functional with 6-311G+dp basis set and a solvation model based on density (SMD) led to accurate pKa values. In particular, calculations performed on a series of 13 differently substituted phenols provided reliable results, with a mean absolute error of 0.3. Furthermore, the model achieves accurate results with -CN and -NO2 substituents, which are usually excluded from computational pKa studies, enabling easy and reliable pKa determination in a wide range of phenols.

Unveiling KuQuinone Redox Species: An Electrochemical and Computational Cross Study.

The study of the electrochemical properties of variegated quinones is a fascinating topic in chemistry. In fact, redox reactions occurring with quinoid scaffolds are essential for most of their applications in biological systems, in photoelectrochemical devices, and in many other fields. In this paper, a detailed investigation of KuQuinones' redox behavior is presented. The distinctiveness of such molecules is the presence in the structure of two condensed naphthoquinone units, which implies the possibility to undergo multiple one-electron reduction processes. Solvent, supporting electrolyte, and hydrogen bond donor species effects have been elucidated. Changing the experimental parameters provoked significant shift of the redox potential for each reduction process. In particular, additions of 2,2,2-trifluoroethanol as a hydrogen bond donor in solution as well as Lewis acid coordination were crucial to obtain important shifts of the redox potentials toward more favorable values. UV-vis-NIR spectroelectrochemical experiments and DFT calculations are also presented to clarify the nature of the reduced species in solution.

Artificial photosynthesis: photoanodes based on polyquinoid dyes onto mesoporous tin oxide surface.

Dye-sensitized photoelectrochemical cells represent an appealing solution for artificial photosynthesis, aimed at the conversion of solar light into fuels or commodity chemicals. Extensive efforts have been directed towards the development of photoelectrodes combining semiconductor materials and organic dyes; the use of molecular components allows to tune the absorption and redox properties of the material. Recently, we have reported the use of a class of pentacyclic quinoid organic dyes (KuQuinone) chemisorbed onto semiconducting tin oxide as photoanodes for water oxidation. In this work, we investigate the effect of the SnO2 semiconductor thickness and morphology and of the dye-anchoring group on the photoelectrochemical performance of the electrodes. The optimized materials are mesoporous SnO2 layers with 2.5 µm film thickness combined with a KuQuinone dye with a 3-carboxylpropyl-anchoring chain: these electrodes achieve light-harvesting efficiency of 93% at the maximum absorption wavelength of 533 nm, and photocurrent density J up to 350 µA/cm2 in the photoelectrochemical oxidation of ascorbate, although with a limited incident photon-to-current efficiency of 0.075%. Calculations based on the density functional theory (DFT) support the role of the reduced species of the KuQuinone dye via a proton-coupled electron transfer as the competent species involved in the electron transfer to the tin oxide semiconductor. Finally, a preliminary investigation of the photoelectrodes towards benzyl alcohol oxidation is presented, achieving photocurrent density up to 90 µA/cm2 in acetonitrile in the presence of N-hydroxysuccinimide and pyridine as redox mediator and base, respectively. These results support the possibility of using molecular-based materials in synthetic photoelectrochemistry.

Similar, Yet Different: Long-Range Metal-Metal Coupling and Electron-Transfer Processes in Metal-Free 5,10,15,20-Tetra(ruthenocenyl)porphyrin.

The electronic structure, redox properties, and long-range metal-metal coupling in metal-free 5,10,15,20-tetra(ruthenocenyl)porphyrin (H2TRcP) were probed by spectroscopic (NMR, UV-vis, magnetic circular dichroism (MCD), and atmospheric pressure chemical ionization (APCI)), electrochemical (cyclic voltammetry, CV, and differential pulse voltammetry, DPV), spectroelectrochemical, and chemical oxidation methods, as well as theoretical (density functional theory, DFT, and time-dependent DFT, TDDFT) approaches. It was demonstrated that the spectroscopic properties of H2TRcP are significantly different from those in H2TFcP (metal-free 5,10,15,20-tetra(ferrocenyl)porphyrin). Ruthenocenyl fragments in H2TRcP have higher oxidation potentials than the ferrocene groups in the H2TFcP complex. Similar to H2TFcP, we were able to access and spectroscopically characterize the one- and two-electron oxidized mixed-valence states in the H2TRcP system. DFT predicts that the porphyrin π-system stabilizes the [H2TRcP]+ mixed-valence cation and prevents its dimerization, which is characteristic for ruthenocenyl systems. However, formation of the mixed-valence [H2TRcP]2+ is significantly less reproducible than the formation of [H2TRcP]+. DFT and TDDFT calculations suggest the ruthenocenyl fragment dominance in the highest occupied molecular orbital (HOMO) energy region and the presence of the low-energy MLCT (Rc → porphyrin (π*)) transitions in the visible region with energies higher than the predominantly porphyrin-centered Q-bands.

A paper-based electrochemical sensor for H2O2 detection in aerosol phase: Measure of H2O2 nebulized by a reconverted ultrasonic aroma diffuser as a case of study.

The outbreak of COVID-19 is caused by high contagiousness and rapid spread of SARS-CoV-2 virus between people when an infected person is in close contact with another one. In this overall scenario, the disinfection processes have been largely improved. For instance, some countries have approved no-touch technologies by vaporizing disinfectants such as hydrogen peroxide, with the overriding goal to boost the safety of the places. In the era of sustainability, we designed an electrochemical paper-based device for the assessment of hydrogen peroxide nebulized by a cost-effective ultrasonic aroma diffuser. The paper-based sensor was fabricated by modifying via drop-casting a filter paper-based screen-printed electrode with a dispersion of carbon black-Prussian Blue nanocomposite, to assess the detection of hydrogen peroxide at -0.05 V vs Ag/AgCl. The use of paper-based modified screen-printed electrode loaded with phosphate buffer allowed for monitoring the concentration of hydrogen peroxide in aerosol, without any additional sampling instrument to capture the nebulized solution of hydrogen peroxide at a concentration up to 7% w/w. Hydrogen peroxide, a reconverted ultrasonic aroma diffuser, and the paper-based electrochemical sensor assisted by smartphone have demonstrated how different low-cost technologies are able to supply an useful and cost-effective solution for disinfection procedures.

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.

Enantioselective Desymmetrization of 1,4-Dihydropyridines by Oxidative NHC Catalysis.

The unprecedented desymmetrization of prochiral dialdehydes catalyzed by N-heterocyclic carbenes under oxidative conditions was applied to the highly enantioselective synthesis of 1,4-dihydropyridines (DHPs) starting from 3,5-dicarbaldehyde substrates. Synthetic elaboration of the resulting 5-formyl-1,4-DHP-3-carboxylates allowed for access to the class of pharmaceutically relevant 1,4-DHP-3,5-dicarboxylates (Hantzsch esters). DFT calculations suggested that the enantioselectivity of the process is determined by the transition state involving the oxidation of the Breslow intermediate by the external quinone oxidant.

Amphiphilic Porphyrin Aggregates: A DFT Investigation.

Owing to the attractive potential applications of porphyrin assemblies in photocatalysis, sensors, and material science, studies presently concerning porphyrin aggregation are widely diffused. π-π stacking, H-bonding, metal coordination, hydrophobic effect, and electrostatic forces usually drive porphyrin interaction in solution. However, theoretical studies of such phenomena are still limited. Therefore, a computational examination of the different porphyrin aggregation approaches is proposed here, taking into account amphiphilic [5-{4-(3-trimethylammonium)propyloxyphenyl}-10,15,20-triphenylporphyrin] chloride, whose aggregation behavior has been previously experimentally investigated. Different functionals have been adopted to investigate the porphyrin dimeric species, considering long-range interactions. Geometry optimization has been performed, showing that for the compound under analysis, H-type and cation-π dimers are the most favored structures that likely co-exist in aqueous solution. Of note, frontier orbital delocalization showed an interesting interaction between the porphyrin units in the dimer at the supramolecular level.

Corroles at the Real Solid-Liquid Interface: In Situ STM Investigation of a Water-Soluble Corrole Layer Deposited onto Au(111).

Corrole derivatives have been recently employed in many applications at the solid-liquid interface. Therefore, the structural arrangement of the molecular layers in direct contact with the liquid is of fundamental interest. We investigated in solution the deposition of molecular layers of the previously prepared water-soluble phosphorus complex of a 2-sulfonato-10-(4-sulfonatophenyl)-5,15-dimesitylcorrole [see synthesis in our previous paper, M. Naitana et al., Chem. Eur. J. 2017, 23, 905-916]. The layer formation of P corroles onto the Au(111) surface was monitored by STM in situ, that is, with the substrate immersed in the solution. Marked differences in the morphology between the organic layer formed on the substrate and that deposited after solvent evaporation (drop casting) are reported. In particular, the coating of gold was more effective and stable in the presence of liquid. Preservation of functionality of the corrole molecules after adsorption was verified. This result validates the relevance of corrole layers at the solid-liquid interface to exploit the peculiar properties of these molecules in real-world applications.

KuQuinones Equilibria Assessment for Biomedical Applications.

A small library of pentacyclic quinoid compounds, called KuQuinones (KuQs), has been prepared through a one-pot reaction. KuQuinones complex structure is made up by two naphthoquinone units connected by a five-membered ring. Due to KuQs structural features, keto-enol tautomerization in solution likely occurs, leading to the generation of four different species, i.e., the enol, the enolate, the external enol and the diquinoid species. The interchange among KuQ tautomers leads to substantial spectral variations of the dye depending on the experimental conditions used. The comprehension of tautomeric equilibria of this new class of quinoid compounds is strongly required in order to explain their behavior in solution and in biological environment. UV-vis, 1H NMR spectroscopies, and DFT calculations resulted appropriate tools to understand the nature of the prevalent KuQuinone species in solution. Moreover, due to the structural similarity of KuQuinones with camptothecin (CPT), a largely used anticancer agent, KuQs have been tested against Cisplatin-resistant SKOV3 and SW480 cancer cell lines. Results highlighted that KuQs are highly active toward the analyzed cell lines and almost nontoxic for healthy cell, indicating a high specific activity.

KuQuinones: a ten years tale of the new pentacyclic quinoid compound.

Quinones are widespread in nature, as they participate, mainly as redox mediators, in several biochemical processes. Up to now, various synthetic quinones have been recommended in the literature as leading molecules in energy, biomedical and catalytic fields. In this brief review, we retraced our research activity in the last ten years, mainly dedicated to the study of a new class of peculiar pentacyclic conjugated quinoid compounds, synthesized in our group. In particular, their application as sensitive materials in photoelectrochemical devices and in biosensors, as photocatalysts in selective oxidation reactions, and their anticancer activity is here reviewed.

A Stoichiometric Solvent-Free Protocol for Acetylation Reactions.

Considering the remarkable relevance of acetylated derivatives of phenols, alcohols, and aryl and alkyl thiols in different areas of biology, as well as in synthetic organic chemistry, a sustainable solvent-free approach to perform acetylation reactions is proposed here. Acetylation reactions are classically performed using excess of acetic anhydride (Ac2O) in solvent-free conditions or by eventually working with stoichiometric amounts of Ac2O in organic solvents; both methods require the addition of basic or acid catalysts to promote the esterification. Therefore, they usually lead to the generation of high amounts of wastes, which sensibly raise the E-factor of the process. With the aim to develop a more sustainable system, a solvent-free, stoichiometric acetylation protocol is, thus, proposed. The naturally occurring phenol, thymol, can be converted to the corresponding-biologically active-ester with good yields, in the presence of 1% of VOSO4. Interestingly, the process can be efficiently adopted to synthesize other thymyl esters, as well as to perform acetylation of alcohols and aryl and alkyl thiols. Remarkably, a further improvement has been achieved replacing Ac2O with its greener alternative, isopropenyl acetate (IPA).

Tailored Functionalization of Natural Phenols to Improve Biological Activity.

Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols' anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.

Photoanodes for water oxidation with visible light based on a pentacyclic quinoid organic dye enabling proton-coupled electron transfer.

A pentacyclic quinoid dye, KuQ(O)3OH, combining (i) extended visible absorption up to 600 nm, (ii) excited state reduction potential >2 V vs. NHE, and (iii) a photoinduced proton-coupled electron transfer mechanism, has been used for the fabrication of dye-sensitized SnO2 photoanodes integrating a ruthenium polyoxometalate water oxidation catalyst. The resulting photoelectrode SnO2|KuQ(O)3OH|Ru4POM displays a light harvesting efficiency up to 90% in the range 500-600 nm, an onset potential as low as 0.2 V vs. NHE at pH 5.8, photoinduced oxygen evolution with a faradaic efficiency of 70 ± 15% and an absorbed-photon-to-current efficiency up to 0.12 ± 0.01%.

ß-Arylethynyl substituted silver corrole complexes.

Silver corrolates are attractive compounds from both practical and theoretical points of view. Indeed, they play a key role in peripheral functionalization reactions occurring at the macrocycle, enabling high-yield and regioselective group insertions useful to further elaborate the molecular skeleton. In parallel, the Janus innocent or noninnocent behavior of the corrole ligand in these complexes makes their description particularly challenging. Herein, we report properties for a series of silver 3,17-disubstituted triarylcorrole complexes with various functionalities (halogens or different phenylethynyl units) that deeply affect the electron density in the macrocyclic ligand, with obvious repercussions on the observed spectral characteristics. The compounds were obtained in yields of 54-92% by applying the Stille coupling reaction with the appropriate tributylethynyl stannane. Among the complexes prepared was a derivative bearing two terminal acetylenic units which opens the way to "click" reactions for new corrole-based architectures. This corrole was structurally characterized by single crystal X-ray crystallography. The addition of substituted ethynyl groups resulted in red-shifts of the electronic absorption spectra, the largest of which was observed for the compound with two ß-NO2-Ph-C[triple bond, length as m-dash]C substituents. The remarkable influence of the NO2 groups on the electron density of this macrocycle was further demonstrated by electrochemical measurements, where an easier reduction of this complex derivative was observed as compared to the others. DFT calculations showed full delocalization over the entire p-nitrophenylethynyl unit of 5, largely affecting orbital distributions and the corresponding electronic absorptions. Although a variation of the ß-substituents dramatically modifies the Soret- and Q-band positions towards lower energies for all the examined complexes, the saddling of the macrocycle resulting from functionalization is only moderate. The collected results suggest the description of these compounds as AgIII-corrolate3-, a metallocorrole with an innocent macrocyclic ligand.