Asymmetric photoenzymatic incorporation of fluorinated motifs into olefins.

Enzymes capable of assimilating fluorinated feedstocks are scarce. This situation poses a challenge for the biosynthesis of fluorinated compounds used in pharmaceuticals, agrochemicals, and materials. We developed a photoenzymatic hydrofluoroalkylation that integrates fluorinated motifs into olefins. The photoinduced promiscuity of flavin-dependent ene-reductases enables the generation of carbon-centered radicals from iodinated fluoroalkanes, which are directed by the photoenzyme to engage enantioselectively with olefins. This approach facilitates stereocontrol through interaction between a singular fluorinated unit and the enzyme, securing high enantioselectivity at ß, γ, or δ positions of fluorinated groups through enzymatic hydrogen atom transfer-a process that is notably challenging with conventional chemocatalysis. This work advances enzymatic strategies for integrating fluorinated chemical feedstocks and opens avenues for asymmetric synthesis of fluorinated compounds.

Influence of chemical structures on reduction rates and defluorination of fluoroarenes during catalytic reduction using a rhodium-based catalyst.

Continuous growth in fluoroarene production has led to environmental pollution and health concerns owing to their persistence, which is attributed to the stable C-F bond in their structures. Herein, we investigated fluoroarene decomposition via hydrodefluorination using a rhodium-based catalyst, focusing on the effects of the chemical structure and functional group on the defluorination yield. Most compounds, except (pentafluoroethyl)benzene, exhibited full or partial reduction with pseudo-first-order rate constants in the range of 0.002-0.396 min-1 and defluorination yields of 0%-100%. Fluoroarenes with hydroxyl, methyl, and carboxylate groups were selected to elucidate how hydrocarbon and oxygen-containing functional groups influence the reaction rate and defluorination. Inhibition of the reaction rate and defluorination yield based on functional groups increased in the order of hydroxyl < methyl < carboxylate, which was identical to the order of the electron-withdrawing effect. Fluoroarenes with polyfluoro groups were also assessed; polyfluoro groups demonstrated a different influence on catalyst activity than non-fluorine functional groups because of fluorine atoms in the substituents undergoing defluorination. The reaction kinetics of (difluoromethyl)fluorobenzenes and their intermediates suggested that hydrogenation and defluorination occurred during degradation. Finally, the effects of the type and position of functional groups on the reaction rate and defluorination yield were investigated via multivariable linear regression analysis. Notably, the electron-withdrawing nature of functional groups appeared to have a greater impact on the defluorination yield of fluoroarenes than the calculated C-F bond dissociation energy.

Discovery of a new 1-(phenylsulfonyl)-1H-indole derivative targeting the EphA2 receptor with antiproliferative activity on U251 glioblastoma cell line.

In our continuing effort devoted at developing agents targeting the EphA2 receptor by means of protein-protein interaction (PPI) inhibitors, we report here the design and synthesis of a new class of l-ß-homotryptophan conjugates of 3-ß-hydroxy-Δ5-cholenic acid bearing a set of arylsulfonyl substituents at the indole nitrogen atom. An extensive structure-activity relationship (SAR) analysis indicates that the presence of a bulky lipophilic moiety at the indole nitrogen is fundamental for improving potency on the EphA2 receptor, while abrogating activity on the EphB1-EphB3 receptor subtypes. A rational exploration, guided by the combined application of an experimental design on σp and π physicochemical descriptors and docking simulations, led to the discovery of UniPR1454, a 1-(4-(trifluoromethyl)phenyl)sulfonyl derivative acting as potent and competitive EphA2 antagonist able to inhibit ephrin-A1 dependent signals and to reduce proliferation of glioblastoma (U251) cell line at micromolar concentration.

Synthetic strategy for the production of electrically polarized polyvinylidene fluoride-trifluoroethylene-co-polymer osseo-functionalized with hydroxyapatite scaffold.

The physiological mechanism of bone tissue regeneration is intricately organized and involves several cell types, intracellular, and extracellular molecular signaling networks. To overcome the drawbacks of autografts and allografts, a number of synthetically produced scaffolds have been manufactured by integrating ceramics, polymers, and their hybrid-composites. Considering the fact that natural bone is composed primarily of collagen and hydroxyapatite, ceramic-polymer composite materials seem to be the most viable alternative to bone implants. Here, in this experimental study, copolymer PVDF-TrFE has been amalgamated with HA ceramics to produce composite scaffolds as bone implants. In order to fabricate PVDF-TrFE-HA (polyvinylidene fluoride-trifluoroethylene-hydroxyapatite) composite scaffolds, solvent casting-particulate leaching technique was devised. Two scaffold specimens were produced, with different PVDF-TrFE and HA molar ratios (70:30 and 50:50), and then electrically polarized to observe the subsequent polarization impact on the tissue growth and the suppression of bacterial cell proliferation. Both the specimens underwent characterization to analyze their biocompatibility and bactericidal activities. The bacterial culture of Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) bacteria on the composites was studied to understand the antibacterial characteristics. Moreover, MG63 cells cultured on these as-formed composites provided information about osteogenesis. Improved osteogenesis and antibacterial efficacy were observed on both the composites. However, the composite with 70 wt% PVDF-TrFE and 30 wt% HA showed a higher bactericidal effect as well as osteogenesis. It was found that PVDF-TrFE-HA-based biomaterials have the potential for bone tissue engineering applications.

Oxidation pathways and kinetics of the 1,1,2,3-tetrafluoropropene (CF2CF-CH2F) reaction with Cl-atoms and subsequent aerial degradation of its product radicals in the presence of NO.

To give a comprehensive account of the environmental acceptability of 1,1,2,3-tetrafluoropropene (CF2CF-CH2F) in the troposphere, we have examined the oxidation reaction pathways and kinetics of CF2CF-CH2F initiated by Cl-atoms using the second-order Møller-Plesset perturbation (MP2) theory along with the 6-31+G(d,p) basis set. We also performed single-point energy calculations to further refine the energies at the CCSD(T) level along with the basis sets 6-31+G(d,p) and 6-311++G(d,p). The estimation of the relative energies and thermodynamic parameters of the CF2CF-CH2F + Cl reaction clearly shows that Cl-atom addition reaction pathways are more dominant compared to H-abstraction reaction pathways. The value of the rate coefficient for each reaction channel is calculated using the conventional transition state theory (TST) over the temperature range of 200-1000 K at 1 atm. The estimated overall rate coefficients for the title reaction are found to be 1.10 × 10-12, 1.21 × 10-10, and 1.13 × 10-8 cm3 per molecule per s via the respective calculation methods viz. MP2/6-31+G(d,p), CCSD(T)//MP2/6-31+G(d,p), and CCSD(T)/6-311++G(d,p)//MP2/6-31+G(d,p), at 298.15 K. Moreover, the calculated rate coefficients and percentage branching ratio values suggest that the Cl-atom addition reaction at the ß-carbon atom is more preferable to that of the α-carbon addition to CF2CF-CH2F. Based on the rate coefficient values calculated by the three different methods, the atmospheric lifetime for the title reaction at 298.15 K is estimated. The radiative efficiency (RE) and Global Warming Potential (GWP) results of the title molecule show that its GWP would be negligible. Further, we have explored the degradation of its product radicals in the presence of O2 and NO. From the degradation results, we have found that CF2(Cl)COF, FCOCH2F, FCFO and FCOCl are formed as stable end products along with various radicals such as ˙CF2Cl and ˙CH2F. Therefore, these findings of kinetic and mechanistic data can be applied to the development and implementation of a novel CFC replacement.

Nonstoichiometric Direct Arylation Polymerization of Octafluorobiphenyl with 2,7-Diiodofluorene for Regulating CH Terminals of π-Conjugated Polymer.

Nonstoichiometric direct arylation polycondensation of 2,2',3,3',5,5',6,6'-octafluorobiphenyl with excess of 2,7-diiodo-9,9-dioctyl-9H-fluorene is demonstrated. Pd/Ag dual-catalyst system under water/2-methyltetrahydrofuran biphasic conditions enables direct arylation under mild conditions and promotes the intramolecular transfer of a Pd catalyst walking through the fluorene moiety. The nonstoichiometric direct arylation polycondensation under the optimized reaction conditions produces the corresponding π-conjugated polymer with a high molecular weight and terminal octafluorobiphenyl units at both ends.

Canister valve and actuator deposition in metered dose inhalers formulated with low-GWP propellants.

A challenge in pressurised metered-dose inhaler (pMDI) formulation design is management of adhesion of the drug to the canister wall, valve and actuator internal components and surfaces. Wall-material interactions differ between transparent vials used for visual inspection and metal canister pMDI systems. This is of particular concern for low greenhouse warming potential (GWP) formulations where propellant chemistry and solubility with many drugs are not well understood. In this study, we demonstrate a novel application of X-ray fluorescence spectroscopy using synchrotron radiation to assay the contents of surrogate solution and suspension pMDI formulations of potassium iodide and barium sulphate in propellants HFA134a, HFA152a and HFO1234ze(E) using aluminium canisters and standard components. Preliminary results indicate that through unit life drug distribution in the canister valve closure region and actuator can vary significantly with new propellants. For solution formulations HFO1234ze(E) propellant shows the greatest increase in local deposition inside the canister valve closure region as compared to HFA134a and HFA152a, with correspondingly reduced actuator deposition. This is likely driven by chemistry changes. For suspension formulations HFA152a shows the greatest differences, due to its low specific gravity. These changes must be taken into consideration in the development of products utilising low-GWP propellants.

Metered dose inhalers in the transition to low GWP propellants: what we know and what is missing to make it happen.

INTRODUCTION: The urgency to replace the propellants currently in use with the new sustainable ones has given rise to the need for investigation and reformulation of pMDIs. AREAS COVERED: The reformulation requires in-depth knowledge of the physico-chemical characteristics of the new propellants, which impact the atomization capacity and the plume geometry. Among the investigated propellants, HFA 152a, due to its lower vapor pressure and higher surface tension compared to HFA 134a, deliver larger particles and has a higher solvent capacity toward lipophilic drugs. On the other hand, HFO 1234ze has properties more similar to HFA 134a, but showed lower reproducibility of the generated spray, indicating a possible high susceptibility to variation in the consistency of the dose delivered. In addition, the device components currently in use are compatible with the new propellants. This allowed promising preliminary results in the re-formulation of pMDIs by academia and pharma companies. However, there is little information about the clinical studies required to allow the marketing of these new products. EXPERT OPINION: Overall, studies conducted so far show that the transition is technically possible, and the main obstacle will be represented by the investment required to put the product on the market.

A Novel Azo-Linked Polymer Bearing Trifluoromethyl Groups for I2 Capture.

In this work, a novel three nitro-group-bearing monomer 3,6-dinitro-9-(2-trifluoromethyl-4-nitrophenyl)-carbazole (Car-3NO2 -CF3 ) via a CN coupling reaction between 3,6-dinitro-9H-carbazole (Car-2NO2 ) and 2-chloro-5-nitrobenzotrifluoride is synthesized, and obtained single crystal and single crystal analysis data for this compound. The crystal system of Car-3NO2 -CF3 is monoclinic and it has a P 21/c space group. This new monomer (Car-3NO2 -CF3 ) is also utilized to synthesize a novel azo-linked polymer (Azo-Car-CF3 ). The trifluoromethyl group has polar CF bonds, and thus it is an effective functional group for the capture of iodine. Azo-Car-CF3 has great thermal stability with a mass loss of only 10% at 414 °C, as well as good chemical stability as is demonstrated by its low solubility in common organic solvents such as tetrahydrofuran (THF), acetone, methanol, ethanol, and N,N-dimethylformamide (DMF). The specific surface area of Azo-Car-CF3 can reach as high as 335 m2  g-1 . Azo-Car-CF3 exhibits an excellent capacity for iodine adsorption and can reach up to 1198 mg g-1 in cyclohexane solution, and its adsorption capacity for iodine vapor can get to 2100 mg g-1 . In addition, ethanol can be used to trigger the release of the captured iodine to be easily released from Azo-Car-CF3 .

A straightforward access to trifluoromethylated natural products through late-stage functionalization.

Covering: 2011 to 2021Trifluoromethyl (CF3)-modified natural products have attracted increasing interest due to their magical effect in binding affinity and/or drug metabolism and pharmacokinetic properties. However, the chemo and regioselective construction of natural products (NPs) bearing a CF3 group still remains a long-standing challenge due to the complex chemical scaffolds and diverse reactive sites of NPs. In recent years, the development of late-stage functionalization strategies, including metal catalysis, organocatalysis, light-driven reactions, and electrochemical synthesis, has paved the way for direct trifluoromethylation process. In this review, we summarize the applications of these strategies in the late-stage trifluoromethylation of natural products in the past ten years with particular emphasis on the reaction model of each method. We also discuss the challenges, limitations, and future prospects of this approach.

Microextraction and Determination of Poly- and Perfluoroalkyl Substances, Challenges, and Future Trends.

Per- and polyfluoroalkyl substances (PFAS) are fluorocarbon compounds in which hydrogen atoms have been partly or entirely replaced by fluorine. They have a very wide range of applications, while they are persistent in the environment and exhibit bioaccumulative and toxic properties. Neither chemical nor biological mechanisms can decompose PFAS due to their strong C-F bonds. PFAS have shown adverse effects on various organisms, even at trace levels. Accordingly, highly sensitive and selective analytical methods are required for their tracing in biological and environmental matrices. The physicochemical properties of PFAS like surfactant characteristics and high-water solubility are unique and different from other known pollutants. Accordingly, the number of articles on the analysis of PFAS is less than the other well-known contaminants. The routine PFAS sample preparation methods (like solvent extraction) coupled with chromatographic systems, face challenges such as high limits of detection, need for laborious derivatization, limited selectivity, and expensive instrumentation. Recent efforts to address these limitations have aroused considerable attention to the development of microextraction techniques, which are consistent with the principles of green chemistry and can be made easily portable and automated. Moreover, these methods have shown enough sensitivity and selectivity for the analysis of different analytes (including PFAS) in a wide range of samples with different matrices. This research aims to review the microextraction methods and detection techniques, applied for the sample pretreatment of PFAS in various matrices, along with a critical discussion of the challenges and potential future trends.

Synthesis, Characterization, and X-ray Crystallography, of the First Cyclohexadienyl Trifluoromethyl Metal Complex (η5-C6H7)Fe(CO)2CF3.

Fluorochemistry is a field of tremendous developments and advances in several areas of science including materials, pharmaceuticals and agriculture. This makes the design and synthesis of fluorine-containing substances highly desirable research targets. The sub-area of synthetic perfluorinated chemistry proportionately attracts widespread interest by applying to all areas of chemistry including organic and inorganic. Particularly, the latter is much underdeveloped as metal complexes with perfluoroalkyl moieties are scarce, with the vast majority of perfluorinated analogs, of long known, halo and alkylated derivatives never having been synthesized. Focusing on the chemistry of trifluoromethyl group, which is the most important in the class of perfluoroalkyls, we set out to explore the possibility of synthesizing and completely characterizing a cyclohexadienyl metal complex. Upon utilizing a number of trifluorometylating reagents, we only arrived at an efficient preparation by the use of Morrison's trifluormethylating reagent. As a result, the new, air- and moisture-sensitive complex (η5-C6H7)Fe(CO)2CF3, was prepared in 71% yield, using a nucleophilic iodo-for-trifluoromethyl substitution, and was completely characterized including by X-ray crystallography.

Recent advances in photocatalytic polyfluoroarylation.

Polyfluoroaryl compounds belong to privileged moieties and engender distinct properties in many pharmaceuticals, agrochemicals, and materials. Over the past decade, considerable seminal reports and reviews have merely paid close attention to fluoroalkylation chemistry, such as trifluoromethylation, difluoroalkylation, perfluoroalkylation, trifluoromethylthiolation or trifluoromethoxylation. Polyfluoroarylation has inevitably lagged somewhat behind its fluoroalkylation counterparts, emanating from a lack of awareness and understanding of the synthetic significance. Together with the renaissance of photochemistry, the photocatalytic polyfluoroarylation using polyfluoroarenes as an inexpensive and easy-available radical precursor has emerged as a topical interest and vibrant area of chemical research. In this review, we have endeavored to present the state-of-the-art in photocatalytic polyfluoroarylation since 2014, and the discussions cover the basic concept, reaction design, mechanistic insight, and research prospects, which are organized by the reaction types. We hope this review will provide a comprehensive overview of this topic and stimulate significant research interest.

Recent advances in transition metal-mediated trifluoromethylation reactions.

Fluorine compounds are known for their abundance in more than 20% of pharmaceutical and agrochemical products mainly due to the enhanced lipophilicity, metabolic stability and pharmacokinetic properties of organofluorides. Consequently, the last decade has seen enormous growth in the incorporation of a trifluoromethyl group into organic motifs. With due significance, this review aims to provide a complete picture of the transition metal-mediated construction of C(sp3, sp2, and sp)-CF3 bonds via C-H/X bond functionalization or addition processes in both aliphatic and aromatic hydrocarbons. Diversified reagents ranging from radical and electrophilic to nucleophilic trifluoromethylating agents and their respective mechanisms have been further deliberated in this comprehensive overview. The comprehensive coverage on this topic is expected to make this review unique and beneficial for further future applications enriching the community towards further improvements in the field of trifluoromethylation reactions, in turn improving the propensity towards further development of agrochemical drugs.

Deoxytrifluoromethylation of Alcohols.

Deoxy-functionalization of alcohols represents a class of reactions that has had a profound impact on modern medicine. In particular, deoxyfluorination is commonly employed as a means to incorporate high-value fluorine atoms into drug-like molecules. Recently, the trifluoromethyl (CF3) group has garnered attention from medicinal chemists due to its ability to markedly improve the pharmaceutical properties of small-molecule drug candidates. To date, however, there remains no general means to accomplish the analogous deoxygenative trifluoromethylation of alcohols. We report herein a copper metallaphotoredox-mediated direct deoxytrifluoromethylation, wherein alcohol substrates are activated in situ by benzoxazolium salts for C(sp3)-CF3 bond formation.

Direct C-H Trifluoromethylation of (Hetero)Arenes in Water Enabled by Organic Photoredox-Active Amphiphilic Nanoparticles.

Photoredox-catalyzed chemical conversions are predominantly operated in organic media to ensure good compatibility between substrates and catalysts. Yet, when conducted in aqueous media, they are an attractive, mild, and green way to introduce functional groups into organic molecules. We here show that trifluoromethyl groups can be readily installed into a broad range of organic compounds by using water as the reaction medium and light as the energy source. To bypass solubility obstacles, we developed robust water-soluble polymeric nanoparticles that accommodate reagents and photocatalysts within their hydrophobic interior under high local concentrations. By taking advantage of the high excited state reduction potential of N-phenylphenothiazine (PTH) through UV light illumination, the direct C-H trifluoromethylation of a wide array of small organic molecules is achieved selectively with high substrate conversion. Key to our approach is slowing down the production of CF3 radicals during the chemical process by reducing the catalyst loading as well as the light intensity, thereby improving effectiveness and selectivity of this aqueous photocatalytic method. Furthermore, the catalyst system shows excellent recyclability and can be fueled by sunlight. The method we propose here is versatile, widely applicable, energy efficient, and attractive for late-stage introduction of trifluoromethyl groups into biologically active molecules.

[18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

Synthesis of Crystalline CF3 -Rich Perfluoropolyethers from Hexafluoropropylene Oxide and (Trifluoromethyl)Trimethylsilane.

The synthesis of a CF3 -rich perfluoropolyether (PFPE) is achieved via the fluoride-catalyzed reaction of hexafluoropropylene oxide (HFPO) with (trifluoromethyl)trimethylsilane (TMSCF3 , so-called Ruppert-Prakash reagent). Nucleophilic addition of a CF3 anion to HFPO affords an acyl fluoride via the ring-opening of HFPO, followed by fluoride elimination. Further addition of CF3 anions to the acyl fluoride gives tertiary perfluoroalkoxide, which attacks HFPO to regenerate an acyl fluoride. Repetition of the sequence via substitution-polymerization affords a new PFPE as a solid, whose structure was confirmed using 19 F NMR spectroscopy, GC-MS, and MALDI-TOF MS analysis. Thermal and X-ray diffraction analyses revealed a crystalline character. To the best of our knowledge, this is the first example of crystalline PFPE. Based on contact-angle measurements, the critical surface tension of this solid PFPE (13.4 mN m-1 ) suggests a water- and oil-repellency of this CF3 -rich PFPE that is higher than that of polytetrafluoroethylene (PTFE; 18.5 mN m-1 ).

Transaminases as suitable catalysts for the synthesis of enantiopure ß,ß-difluoroamines.

Transaminases have shown the ability to catalyze the amination of a series of aliphatic and (hetero)aromatic α,α-difluorinated ketones with high stereoselectivity, thus providing the corresponding ß,ß-difluoroamines in high isolated yields (55-82%) and excellent enantiomeric excess (>99%). It was also observed that these activated substrates could be quantitatively transformed by employing a small molar excess of the amine donor since this amination process was thermodynamically favored. Selected transformations could be scaled up to 500 mg, showing the robustness of this methodology.

Tefluthrin: metabolism, food residues, toxicity, and mechanisms of action.

Tefluthrin is a Type I pyrethroid insecticide widely used all over the world. Residues of tefluthrin in various agricultural and animal-derived products may be related to potential human health risks. Tefluthrin metabolism in mammals involves hydrolysis of the ester bond to form cyclopropane acid and 4-methylbenzyl alcohol moieties, followed by oxidation. In this review manuscript, we provide crucial information regarding the toxicity of pyrethroids and propose natural antioxidants for amelioration poisoning in humans and animals. We call for the rational use of tefluthrin as an agrochemical product and for greater attention to the residual toxicity caused by tefluthrin in primary and succeeding crops. This greater attention is required given the global use of tefluthrin.