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In this work, we describe the synthesis of halogenated pyran analogues of ᴅ-talose using a halo-divergent strategy from known 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-mannopyranose. In solution and in the solid-state, all analogues adopt standard 4C1-like conformations despite 1,3-diaxial repulsion between the F2 and the C4 halogen. Moreover, the solid-state conformational analysis of halogenated pyrans reveals deviation in the intra-annular torsion angles arising from repulsion between the axial fluorine at C2 and the axial halogen at C4, which increases with the size of the halogen at C4 (F < Cl < Br < I). Crystal packing arrangements of pyran inter-halides show hydrogen bond acceptor and nonbonding interactions for the halogen at C4. Finally, density functional theory (DFT) calculations corroborate the preference of talose analogues to adopt a 4C1-like conformation and a natural bonding orbital (NBO) analysis demonstrates the effects of hyperconjugation from C–F antibonding orbitals.

A method for the radical functionalization of 1,2,4‐oxadiazoles using alkyl halides as precursors of radicals is described. The reaction efficiency is determined by potassium tetrafluoropyridinyl thiolate additive, which plays dual role. First, the thiolate converts alkyl halides into more reactive fluorinated aryl sulfides, which undergo photoredox activation of the C−S bond. Second, the thiolate decreases the unproductive loss of alkyl radicals by converting them back to the sulfides. [ABSTRACT FROM AUTHOR]

Poly‐ and perfluoroalkyl substances (PFAS) are a class of persistent organic pollutants whose high stability and appreciable water solubility have led to near‐global contamination. PFAS are bioaccumulative toxins that have been linked to a myriad of disorders and have been detected nearly universally in human blood. Liquid chromatography‐tandem mass spectrometry is the most frequent method used for quantitation, though this typically only measures a few dozen of the >14 000 known PFAS and has been shown to account for a small portion of the total organic fluorine present. Sum parameter methods such as total, extractable, and adsorbable organic fluorine have emerged as alternative measurements for PFAS determination. Combustion ion chromatography has become the preferred method for organofluorine measurement where the sorbent or extract containing PFAS is combusted and the emitted hydrofluoric acid (HF) is a measure of the cumulative organofluorine present. Herein we critically review the types of organofluorine measurement, their separation from the sample matrix, and key parameters of the analytical instrument that affect sensitivity, reproducibility, and recovery with regards to PFAS analysis. [ABSTRACT FROM AUTHOR]

Solutions of 1,3-diketones and 1,3-ketoester derivatives react with fluorine to give the corresponding 2,2-difluoro-1,3-dicarbonyl derivatives in the presence of quinuclidine. Quinuclidine reacts with fluorine in situ to generate a fluoride ion that facilitates limiting enolization processes, and an electrophilic N–F fluorinating agent that is reactive towards neutral enol species.

ABSTRACTMicrobial response to toxic fluoride anion has traditionally been studied by adding inorganic fluoride salts to growth media. Fluoride is known to spontaneously transit the membrane as hydrogen fluoride (HF) and manifests significant toxicity in the cytoplasm. The present study investigated how microbes respond to high levels of HF generated directly in the cytoplasm to better understand potential limits of microbial defluorination of organofluorine compounds. For that purpose, Pseudomonas putida ATCC 12633 was engineered to express a defluorinase enzyme from Delftia acidovorans strain B that had high activity in producing growth-supporting alcohols from organofluorinated compounds of xenobiotic origin. Genome annotation predicted the growth of P. putida ATCC 12633 on all possible chiral products from 2-fluoropropionic acid and α-fluorophenylacetic acid when defluroinases are expressed. The defluorinase was shown to have complete enantioselectivity for (S)-fluoro substrates via experimental and computational modeling methods. The bacterium grew to a high turbidity with stoichiometric release of fluoride from the (S)-enantiomers into the medium. The highest yield of fluoride obtained was 50 mM with 2-fluoropropionic acid as the growth substrate. The growth yield was significantly lowered by 41% with α-fluorophenylacetic acid or 2-fluoropropionic acid compared to (S)-mandelic acid or D-lactic acid, respectively. Fluoride stress was also indicated by longer lag phases, slower growth, and cell morphology changes on fluorinated substrates or the cognate alcohols with NaF in the medium. In total, these studies show the potential for engineering bacterial defluorination of non-natural substrates within limits posed by fluoride stress.IMPORTANCESociety uses thousands of organofluorine compounds, sometimes denoted per- and polyfluoroalkyl substances (PFAS), in hundreds of products, but recent studies have shown some to manifest human and environmental health effects. As a class, they are recalcitrant to biodegradation, partly due to the paucity of fluorinated natural products to which microbes have been exposed. Another limit to PFAS biodegradation is the intracellular toxicity of fluoride anion generated from C-F bond cleavage. The present study identified a broader substrate specificity in an enzyme originally studied for its activity on the natural product fluoroacetate. A recombinant Pseudomonas expressing this enzyme was used here as a model system to better understand the limits and effects of a high level of intracellular fluoride generation. A fluoride stress response has evolved in bacteria and has been described in Pseudomonas spp. The present study is highly relevant to organofluorine compound degradation or engineered biosynthesis in which fluoride anion is a substrate.

Aromatic compounds interact with organozinc reagents under photoredox conditions, leading to the substitution products. The reaction is performed under blue light irradiation via in situ generated organozinc reagents (Barbier conditions), which are oxidized by the photocatalyst, followed by radical attack at the aromatic substrate. The method works with polyfluorinated arenes, 2‐chlorobenzoxazoles, and 2‐sulfonyl‐substituted benzothiazole. [ABSTRACT FROM AUTHOR]

In the last few years, many reagents and protocols have been developed to allow for the efficient fluorofunctionalization of a diverse set of scaffolds ranging from alkanes, alkenes, alkynes, and (hetero)arenes. The concomitant rise of organofluorine chemistry and visible light‐mediated synthesis have synergistically expanded the fields and have mutually benefitted from developments in both fields. In this context, visible light driven formations of radicals containing fluorine have been a major focus for the discovery of new bioactive compounds. This review details the recent advances and progress made in visible light‐mediated fluoroalkylation and heteroatom centered radical generation. [ABSTRACT FROM AUTHOR]

Zinc chelate complexes can be generated in situ from N‐acyl hydrazones by treatment with isopropyl zinc iodide. These complexes couple with alkyl and fluorinated radicals under photoredox conditions. Alkyl radicals were generated from organozinc halides using an organic photocatalyst and afford hydrazines as a result of reductive mode of addition. Fluorinated radicals were formed from perfluorinated alkyl iodides under photoredox conditions leading to fluoroalkylated hydrazones via neutral reaction pathway. [ABSTRACT FROM AUTHOR]

The sulfur‐fluorine partnership occupies a privileged position in fluorine chemistry given the functional versatility that it imparts to organic structures. Despite this, available methodologies to forge S−F bonds are limited compared to C−F bond formation. Here, we describe a synthetic protocol that selectively enables the oxidative halogenation of aliphatic, aromatic, and heteroaromatic thiols to their corresponding SF4Cl, SO2F and SF3 derivatives. Selective oxidation of thiols to either S(IV)‐F or S(VI)‐F compounds is achieved by employing bench‐stable calcium hypochlorite as chlorine surrogate (CLOgen), in the presence of KF as fluoride source. Density functional theory (DFT) calculations provided insight into the mechanistic aspects of the transformation and rationalized the observed isomeric preference towards the SF4Cl derivatives. Ultimately, this glovebox‐free method selectively dispatches three classes of compounds upon reaction condition fine‐tuning. Furthermore, first‐in‐class transformations are reported, including the preparation of aliphatic SF4Cl intermediates, their transformation into aliphatic sulfur pentafluoride analogs, and post‐functionalizations that allow accessing highly complex SF4‐bridged scaffolds. [ABSTRACT FROM AUTHOR]

Atom transfer radical addition of bromonitromethane and 1,2-dibromotetrafluoroethane to alkenes is described. The reaction is performed under blue light irradiation using two catalysts: 4CzIPN and manganese (II) bromide. The cyanoarene photocatalyst serves for the redox activation of starting organic bromide, while the manganese salt facilitates the trapping of the alkyl radical with the formation of the carbon–bromine bond. [ABSTRACT FROM AUTHOR]

Fluorinated small molecules play an important role in the design of bioactive compounds for a broad range of applications. As such, there is strong interest in developing a deeper understanding of how fluorine affects the interaction of these ligands with their targets. Given the small number of fluorinated metabolites identified to date, insights into fluorine recognition have been provided almost entirely by synthetic systems. The fluoroacetyl-CoA thioesterase (FlK) from Streptomyces cattleya thus provides a unique opportunity to study an enzyme-ligand pair that has been evolutionarily optimized for a surprisingly high 106 selectivity for a single fluorine substituent. In these studies, we synthesize a series of analogs of fluoroacetyl-CoA and acetyl-CoA to generate nonhydrolyzable ester, amide, and ketone congeners of the thioester substrate to isolate the role of fluorine molecular recognition in FlK selectivity. Using a combination of thermodynamic, kinetic, and protein NMR experiments, we show that fluorine recognition is entropically driven by the interaction of the fluorine substituent with a key residue, Phe-36, on the lid structure that covers the active site, resulting in an ∼5- to 20-fold difference in binding (KD). Although the magnitude of discrimination is similar to that found in designed synthetic ligand-protein complexes where dipolar interactions control fluorine recognition, these studies show that hydrophobic and solvation effects serve as the major determinant of naturally evolved fluorine selectivity.

A broad range of aliphatic, aromatic, and heterocyclic boronic acids were successfully homologated using trifluorodiazoethane in the presence of BINOL derivatives to provide the corresponding chiral trifluoromethyl containing boronic acid derivatives in high yields and excellent enantioselectivity. The in situ conversion of the chiral transient boronic acids to the corresponding alcohols or β‐CF3 carboxylates are also demonstrated. [ABSTRACT FROM AUTHOR]

The existing technologies in municipal wastewater treatment plants are ineffective in eliminating persistent fluorine-containing contaminants. At the same time, there is an increasing demand for novel organofluorine compounds, particularly in the production of lithium-ion batteries, as well as in the agrochemical and pharmaceutical sectors for more efficient ingredients. This implies that we must account for ongoing changes in the fluorine levels within riverine environments. To determine the fluorine concentration in the water phase of rivers, it is essential to measure both inorganic fluoride and total organofluorine concentrations. These analytes were measured in water samples collected monthly from twelve locations along the Hungarian section of the Danube River during the period from July to December 2023, applying ion-chromatography and combustion ion-chromatography. The concentration of inorganic fluoride ranged from 28 to 76 µg/L, with a median of 45.3 µg/L. The total adsorbable organofluorine concentrations were between 0.22 and 12.5 µg/L, with a median of 2.43 µg/L. To assess the impact of restrictions on the use of PFOA and PFOS compounds, these substances were quantified using a UHPLC-Q-TOF-MS system. A comparison of our data with previously published concentrations in the Danube River reveals a decreasing tendency, justifying the restricted use of these chemicals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Metal pattern formation using vacuum evaporation is an essential technology in various fields such as electronics, photonics, and industrial mass production. An application of selective metal deposition, in which a metal pattern can be prepared by maskless vacuum evaporation, based on the phenomenon of metal atom desorption from the organic surface, is expected as a promising method. However, the surface physical properties that govern the desorption of metals have not been fully clarified. In this study, the metal desorption phenomenon in various organofluorine films with a low surface energy is investigated in detail, and the factors governing the desorption are clarified. It is revealed that metal desorption requires not a low total surface energy but rather the London dispersion component of surface energy as small as 20 mJ m−2, and, moreover, that the surface should have fluidity or high molecular mobility. As typical materials having such physical properties, commercially available mold release agents show efficient desorption with respect to many metals having a low intrinsic vapor pressure such as Au, Ag, Cr, and In. Furthermore, 3D integrated deposition is performed as a demonstration of efficient metal desorption. This highly efficient metal desorption phenomenon is applicable to various fields including electronics. [ABSTRACT FROM AUTHOR]

Fluorine is an element with unusual properties that has found significant utility in the design of synthetic small molecules, ranging from therapeutics to materials. In contrast, only a few fluorinated compounds made by living organisms have been found to date, most of which derive from the fluoroacetate/fluorothreonine biosynthetic pathway first discovered in Streptomyces cattleya While fluoroacetate has long been known to act as an inhibitor of the tricarboxylic acid cycle, the fate of the amino acid fluorothreonine is still not well understood. Here, we show that fluorothreonine can be misincorporated into protein in place of the proteinogenic amino acid threonine. We have identified two conserved proteins from the organofluorine biosynthetic locus, FthB and FthC, that are involved in managing fluorothreonine toxicity. Using a combination of biochemical, genetic, physiological, and proteomic studies, we show that FthB is a trans-acting transfer RNA (tRNA) editing protein, which hydrolyzes fluorothreonyl-tRNA 670-fold more efficiently than threonyl-RNA, and assign a role to FthC in fluorothreonine transport. While trans-acting tRNA editing proteins have been found to counteract the misacylation of tRNA with commonly occurring near-cognate amino acids, their role has yet to be described in the context of secondary metabolism. In this regard, the recruitment of tRNA editing proteins to biosynthetic clusters may have enabled the evolution of pathways to produce specialized amino acids, thereby increasing the diversity of natural product structure while also attenuating the risk of mistranslation that would ensue.

A side-product present in the herbicide pyroxasulfone was synthesized. The construction of a bis(aryloxy)fluoromethane moiety was necessary, for which no existing method was available. We report a simple, new procedure which we applied to the synthesis of some of these unusual structures.

The capacity to defluorinate polyfluorinated organic compounds is a rare phenotype in microbes but is increasingly considered important for maintaining the environment. New discoveries will be greatly facilitated by the ability to screen many natural and engineered microbes in a combinatorial manner against large numbers of fluorinated compounds simultaneously. Here, we describe a low-volume, high-throughput screening method to determine defluorination capacity of microbes and their enzymes. The method is based on selective binding of fluoride to a lanthanum chelate complex that gives a purple-colored product. It was miniaturized to determine biodefluorination in 96-well microtiter plates by visual inspection or robotic handling and spectrophotometry. Chemicals commonly used in microbiological studies were examined to define usable buffers and reagents. Base-catalyzed, purified enzyme and whole-cell defluorination reactions were demonstrated with fluoroatrazine and showed correspondence between the microtiter assay and a fluoride electrode. For discovering new defluorination reactions and mechanisms, a chemical library of 63 fluorinated compounds was screened in vivo with Pseudomonas putida F1 in microtiter well plates. These data were also calibrated against a fluoride electrode. Our new method revealed 21 new compounds undergoing defluorination. A compound with four fluorine substituents, 4-fluorobenzotrifluoride, was shown to undergo defluorination to the greatest extent. The mechanism of its defluorination was studied to reveal a latent microbial propensity to defluorinate trifluoromethylphenyl groups, a moiety that is commonly incorporated into numerous pharmaceutical and agricultural chemicals. [ABSTRACT FROM AUTHOR]

In this work, we describe the synthesis of halogenated pyran analogues of ᴅ-talose using a halo-divergent strategy from known 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-ᴅ-mannopyranose. In solution and in the solid-state, all analogues adopt standard 4 C 1 -like conformations despite 1,3-diaxial repulsion between the F2 and the C4 halogen. Moreover, the solid-state conformational analysis of halogenated pyrans reveals deviation in the intra-annular torsion angles arising from repulsion between the axial fluorine at C2 and the axial halogen at C4, which increases with the size of the halogen at C4 (F < Cl < Br < I). Crystal packing arrangements of pyran inter-halides show hydrogen bond acceptor and nonbonding interactions for the halogen at C4. Finally, density functional theory (DFT) calculations corroborate the preference of talose analogues to adopt a 4 C 1 -like conformation and a natural bonding orbital (NBO) analysis demonstrates the effects of hyperconjugation from C-F antibonding orbitals., (Copyright © 2024, Lessard et al.)

A protocol for performing atom transfer radical addition of activated alkyl chlorides to alkenes is described. The reaction is promoted by blue light in the presence of an organic photocatalyst (3DPA2FBN), serving to generate free radicals, and a copper complex (IMesCuCl), which facilitates the chlorine transfer step. The reaction works efficiently with fluorinated and non‐fluorinated α‐chloroesters. [ABSTRACT FROM AUTHOR]

The construction of carbon‐fluorine bonds is an important yet challenging task in organic synthesis. Transition metal‐catalyzed/‐mediated C−F bond forming processes have recently emerged as a viable strategy and provided access to value‐added monofluorinated compounds. A dramatic increase in fluorination methods using inexpensive and earth‐abundant copper can be seen in the past decade surpassing those using palladium and silver. This review discusses the recent development of Cu‐catalyzed/‐mediated formation of C(sp2)−F and C(sp3)−F bonds. [ABSTRACT FROM AUTHOR]

gem -Difluoroalkenes are readily available fluorinated building blocks, and the fluorine-induced electronic perturbations of the alkenes enable a wide array of selective functionalization reactions. However, many reactions of gem -difluoroalkenes result in a net C–F functionalization to generate monofluorovinyl products or addition of F to generate trifluoromethyl-containing products. In contrast, fluorine-retentive strategies for the functionalization of gem -difluoroalkenes remain less generally developed and is now becoming a rapidly developing area. This review will present the development of fluorine-retentive strategies including electrophilic, nucleophilic, radical, and transition metal catalytic strategies with an emphasis on key physical organic and mechanistic aspects that enable reactivities. 1 Introduction 2 Two-Electron Processes 2.1 Elimination of Allyl Groups 2.2 Electrophilic Addition 2.3 Halonium and Thiiranium Intermediates 2.4 Kinetic Quench of Anionic Intermediates 2.5 Concerted Cycloadditions 3 Radical Processes 3.1 Thermal Activation 3.2 Photoactivation 3.3 Transition-Metal-Mediated 4 Reductions 5 Cross-Coupling Reactions 6 Conclusions [ABSTRACT FROM AUTHOR]

ABSTRACT Perfluorinated carbon atoms in a diether linkage are common in commercial anesthetics, drugs, fungicides, and insecticides. An important chemical group comprising perfluorodiethers is the 2,2-fluoro-1,3-benzodioxole (DFBD) moiety. The fluorine atoms stabilize the molecule by mitigating against metabolism by humans and microbes, as used in drugs and pesticides, respectively. Pseudomonas putida F1 catalyzed defluorination of DFBD at an initial rate of 2,100 nmol/h per mg cellular protein. This is orders of magnitude higher than previously reported microbial defluorination rates with multiply fluorinated carbon atoms. Defluorination rates declined after several hours, and the medium darkened. Significant defluorination activity was observed with cells grown on toluene but not l-arginine. Defluorination required only toluene dioxygenase. Pseudomonas and recombinant Escherichia coli cells expressing toluene dioxygenase oxidized DFBD to DFBD-4,5-dihydrodiol. The dihydrodiol could be oxidized to 4,5-dihydroxy-DFBD via the dihydrodiol dehydrogenase from P. putida F1. The dihydrodiol dehydrated with acid to yield a mixture of 4-hydroxy-DFBD and 5-hydroxy-DFBD. All those metabolites retained the difluoromethylene group; no fluoride or dark color was observed. The major route of DFBD-4,5-dihydrodiol decomposition produced fluoride and 1,2,3-trihydroxybenzene, or pyrogallol, and that was shown to be the source of the dark colors in the medium. A mechanism for DFBD-4,5-dihydrodiol transformation to two fluoride ions and pyrogallol is proposed. The Pseudomonas genome database and other databases revealed hundreds of bacteria with enzymes sharing high amino acid sequence identity to toluene dioxygenase from P. putida F1, suggesting the mechanism revealed here may apply to the defluorination of DFBD-containing compounds in the environment. IMPORTANCE There are more than 9,000 polyfluorinated compounds developed for commercial use, some negatively impacting human health, and they are generally considered to be resistant to biodegradation. Only a limited number of studies have identified microbes with enzymes sufficiently reactive to defluorinate difluoromethylene carbon groups. The present study examined one important group of commercial fluorinated chemicals and showed its rapid defluorination by a bacterium and its key enzyme, a Rieske dioxygenase. Rieske dioxygenases are common in environmental bacteria, and those closely resembling toluene dioxygenase from Pseudomonas putida F1 are candidates for biodegradative defluorination of the common 2,2-fluoro-1,3-benzodioxole (DFBD) moiety.

We synthesize current understanding of the magnitudes and methods for assessing human and wildlife exposures to poly‐ and perfluoroalkyl substances (PFAS). Most human exposure assessments have focused on 2 to 5 legacy PFAS, and wildlife assessments are typically limited to targeted PFAS (up to ~30 substances). However, shifts in chemical production are occurring rapidly, and targeted methods for detecting PFAS have not kept pace with these changes. Total fluorine measurements complemented by suspect screening using high‐resolution mass spectrometry are thus emerging as essential tools for PFAS exposure assessment. Such methods enable researchers to better understand contributions from precursor compounds that degrade into terminal perfluoroalkyl acids. Available data suggest that diet is the major human exposure pathway for some PFAS, but there is large variability across populations and PFAS compounds. Additional data on total fluorine in exposure media and the fraction of unidentified organofluorine are needed. Drinking water has been established as the major exposure source in contaminated communities. As water supplies are remediated, for the general population, exposures from dust, personal care products, indoor environments, and other sources may be more important. A major challenge for exposure assessments is the lack of statistically representative population surveys. For wildlife, bioaccumulation processes differ substantially between PFAS and neutral lipophilic organic compounds, prompting a reevaluation of traditional bioaccumulation metrics. There is evidence that both phospholipids and proteins are important for the tissue partitioning and accumulation of PFAS. New mechanistic models for PFAS bioaccumulation are being developed that will assist in wildlife risk evaluations. Environ Toxicol Chem 2021;40:631–657. © 2020 SETAC [ABSTRACT FROM AUTHOR]

Perfluoropyridine (PFPy) is an organofluorine compound that has been employed for a variety of applications, from straightforward chemical synthesis to more advanced functions, such as fluorinated networks and polymers. This can be directly attributed to the highly reactive nature of PFPy, especially towards nucleophilic aromatic substitution (SNAr). The aim of this review is to highlight the discovery and synthesis of PFPy, discuss its reactive nature towards SNAr, and to summarize known reports of the utilization and thermal analysis of PFPy containing fluoropolymers and fluorinated network materials.

Frustrated Lewis pairs consisting of diphenylphosphino and boryl groups located at the ortho‐position can trap difluorocarbene affording stable zwitterionic adducts. The reaction can be reversed to release difluorocarbene at elevated temperatures. [ABSTRACT FROM AUTHOR]

Solutions of 1,3-diketones and 1,3-ketoester derivatives react with fluorine to give the corresponding 2,2-difluoro-1,3-dicarbonyl derivatives in the presence of quinuclidine. Quinuclidine reacts with fluorine in situ to generate a fluoride ion that facilitates limiting enolization processes, and an electrophilic N-F fluorinating agent that is reactive towards neutral enol species., (Copyright © 2024, Hampton et al.)

Importance: Society uses thousands of organofluorine compounds, sometimes denoted per- and polyfluoroalkyl substances (PFAS), in hundreds of products, but recent studies have shown some to manifest human and environmental health effects. As a class, they are recalcitrant to biodegradation, partly due to the paucity of fluorinated natural products to which microbes have been exposed. Another limit to PFAS biodegradation is the intracellular toxicity of fluoride anion generated from C-F bond cleavage. The present study identified a broader substrate specificity in an enzyme originally studied for its activity on the natural product fluoroacetate. A recombinant Pseudomonas expressing this enzyme was used here as a model system to better understand the limits and effects of a high level of intracellular fluoride generation. A fluoride stress response has evolved in bacteria and has been described in Pseudomonas spp. The present study is highly relevant to organofluorine compound degradation or engineered biosynthesis in which fluoride anion is a substrate., Competing Interests: The authors declare no conflict of interest.

Decarboxylative arylation of α,α-difluoro-β-ketoacid salts with diaryliodonium(III) salts has been developed to synthesize α-aryl-α,α-difluoromethyl ketones, which are attractive synthetic intermediates for various difluorobenzyl units. This additive-free arylation represents an alternative approach to conventional synthetic methods that rely on transition metal catalysts and/or organometallic compounds. The reaction involves sequential ligand exchange of difluoroketoacid with tosylate ligand of diaryliodonium salt, followed by decarboxylative ligand coupling. Various functional groups, including ester, nitro, cyano, heteroarenes, and aryl halide groups, were tolerated during the present reaction. The resulting α-aryl-α,α-difluoromethyl ketones can be transformed into the corresponding esters, amides, and difluoromethyl compounds, which are commonly found in biologically active compounds.

There is intense interest in removing fluorinated compounds from the environment, environments are most efficiently remediated by microbial enzymes, and defluorinating enzymes are readily monitored by fluoride determination. Fluorine is the most electronegative element. Consequently, all mechanisms of enzymatic C-F bond cleavage produce fluoride anion, F - . Therefore, methods for the determination of fluoride are critical for C-F enzymology and apply to any fluorinated organic compounds, including PFAS, or per- and polyfluorinated alkyl substances. The biodegradation of most PFAS chemicals is rare or unknown. Accordingly, identifying new enzymes, or re-engineering the known defluorinases, will require rapid and sensitive methods for measuring fluoride in aqueous media. Most studies currently use ion chromatography or fluoride specific electrodes which are relatively sensitive but low throughput. The methods here describe refashioning a drinking water test to efficiently determine fluoride in enzyme and cell culture reaction mixtures. The method is based on lanthanum alizarin complexone binding of fluoride. Reworking the method to a microtiter well plate format allows detection of as little as 4 nmol of fluoride in 200 μL of assay buffer. The method is amenable to color imaging, spectrophotometric plate reading and automated liquid handling to expedite assays with thousands of enzymes and/or substrates for discovering and improving enzymatic defluorination., (Copyright © 2024. Published by Elsevier Inc.)

The effect of solvents has been found as a crucial factor in determining the regioselectivity of the hydroxyalkylation of indole with trifluoroacetaldehyde hemiacetals. The appropriate selection of the solvent ensured to achieve absolute N1 or C3 regio/chemoselectivity of the reaction depending on the polarity and dielectric constant of the medium. Reaction conditions were optimized considering the effect of solvent, including temperature, time, and molar ratio of reactants to base. In order to rationalize this effect, density functional theory has been employed in which implicit as well as explicit role of solvent was studied, which were further validated with in situ 1H NMR spectroscopy experiments. The comparison of transition states derived from the implicit calculations revealed that the lowest energy path of the reaction in dimethyl sulfoxide (DMSO) leads to product formation with N-selectivity. Further DFT calculations on explicit interactions of indole with DMSO indicated enhanced nucleophilicity on the N atom compared to that of C3 atom, which is evident from the calculated electrostatic potential (ESP) fit charges of these complexes. These findings appear to support the experimental data and explain the N-selectivity in DMSO. [ABSTRACT FROM AUTHOR]

A catalytic method for the incorporation of an SCF3 group to tryptamine derivatives was developed via a sulfide‐catalyzed cascade trifluoromethylthiolation‐cyclization. A series of C(3)‐CF3S pyrrolidinoindolines were obtained in moderate to good yields under mild conditions. Furthermore, some enantioselectivity was observed when using chiral sulfide thiocineole as a catalyst. [ABSTRACT FROM AUTHOR]

A practical synthesis of (Z)-2-bromo-2-CF3-vinyl phenyl sulfide from 2-CF3-vinyl phenyl sulfide was achieved using bromine (Br2) in the presence of LiBr and LiOAc in AcOH in one flask. This method affords a stereodefined product in high yield under mild conditions. The synthetic application of the product was briefly examined, providing a wide range of Sonogashira cross-coupling products using terminal acetylenes as a coupling partner. [ABSTRACT FROM AUTHOR]

Owing to the strength of the C−F bond, the ‘direct’ preparation of Grignard reagents, i.e., the interaction of elemental magnesium with an organic halide, typically in an ethereal solvent, fails for bulk magnesium and organofluorine compounds. Previously described mechanochemical methods for preparing Grignard reagents have involved ball milling powdered magnesium with organochlorines or bromines. Activation of the C−F bond through a similar route is also possible, however. For example, milling 1- and 2-fluoronaphthalene with an excess of magnesium metal for 2 h, followed by treatment with FeCl3 and additional milling, produces the corresponding binaphthalenes, albeit in low yields (ca. 20%). The yields are independent of the particular isomer involved and are also comparable to the yields from corresponding the bromonaphthalenes. These results may reflect similar charges that reside on the α-carbon in the naphthalenes, as indicated by density functional theory calculations.

Presently, the world depends on a wide variety of new materials based on organofluorine compounds. These compounds can be used as surfactants, high resistance polymers, liquid crystals, agrochemicals, radiopharmaceuticals for positron emission tomography, and drugs. However, the selective formation of C–F bonds remains a challenge. This study reviews our knowledge of organofluorine compounds and describes conventional and modern selective fluorination methods for obtaining these compounds. Here, we highlight the most common fluorination reagents and describe the fluorination reactions. This review is organized by the type of fluorine transfer: nucleophilic, electrophilic, and enzymatic

Nuclear magnetic resonance is a technique that is widely used for elucidating and characterizing organic substances. Organofluorine substances have applications in many areas from drugs to liquid crystals, but their NMR spectra are often challenging due to fluoride coupling with other nuclei. For this reason, NMR spectra of this class of substances are not commonly covered in undergraduate and graduate chemistry courses and related fields. Thus, the aim of this work was the presentation and discussion of 1H, 13C, and 19F NMR spectra of eleven organofluorine substances which, in the case of 1H and 13C nuclei, showed classic patterns of first-order coupling and the effects of the fluorine nucleus in different chemical and magnetic environments. In addition, the observation of long distance coupling constants was possible through the use of apodization functions in the processing of the spectra. It is expected that the examples presented herein can be utilized and discussed in undergraduate and graduate NMR spectroscopy disciplines and thus improve the teaching and future research of organofluorine compounds.

A new method for the preparation of α-fluorovinyl thioethers is reported which involves the hydrofluorination of alkynyl sulfides with 3HF·Et3N, a process that requires Lewis acid activation using BF3·Et2O and TiF4. The method gives access to a range of α-fluorovinyl thioethers, some in high stereoselectivity with the Z-isomer predominating over the E-isomer. The α-fluorovinyl thioether motif has prospects as a steric and electronic mimetic of thioester enols and enolates, important intermediates in enzymatic C–C bond forming reactions. The method opens access to appropriate analogues for investigations in this direction.

Abstract: Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all‐cis‐2,3,5,6‐tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all‐cis‐2,3,5,6‐tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn‐amino‐alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans‐halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 23–26 and the preferred conformations of these α‐fluoroamides were explored by DFT, X‐ray structure and 1H–19F HOESY NMR analysis. [ABSTRACT FROM AUTHOR]

The synthesis of 6( R )- and 6( S )- fluoropenibruguieramine As has been achieved, employing the elegant strategy developed by Kim and co-workers. Single diastereomers were formed via the key intramolecular aldol reaction, and both of the products were unambiguously confirmed by X-ray diffraction crystallography. This reaction shows that the fluorine amide effect could not compete with the memory of chirality (MOC) effect, thus further demonstrating the powerfulness of MOC effect in asymmetric synthesis. The biological testing carried out in this work indicates that the principal of antibacterial activity of the natural extract is probably not penibruguieramine A. [ABSTRACT FROM AUTHOR]

Monofluoroalkenes have found wide application in organic chemistry, medicinal chemistry, and materials science. This review summarizes the most recent advances made regarding the preparation of monofluoroalkenes, covering the period between October 2010 and September 2017. This review is divided in three main parts, one for each possible substitution pattern, namely di-, tri-, and tetrasubstituted. Then, for each class, further subclassification is made according to the reaction type. 1 Introduction 2 Disubstituted Monofluoroalkenes 2.1 Disubstituted α-Monofluoroalkenes 2.2 Disubstituted β-Monofluoroalkenes 3 Trisubstituted Monofluoroalkenes 4 Tetrasubstituted Monofluoroalkenes 5 Conclusions [ABSTRACT FROM AUTHOR]

A fluorine-containing difunctional benzoxazine is synthesized by hydrosilylation of a monofunctional benzoxazine based on o-allylphenol and p-fluoroaniline. Besides the intramolecular and intermolecular hydrogen bonding associated with the nitrogen and oxygen atoms in the oxazine ring, specific self-complementary intermolecular ArF···HO hydrogen bonding is formed in the polymerization of the benzoxazine, which leads to the resultant polybenzoxazine possessing a broad glass transition temperature range and showing two not well-separated transitions. Based on the two glass transition temperatures, the polybenzoxazine exhibits triple-shape-memory behaviors by manipulating temperature and strain in the shape fixing process under tensile and bending modes. The dynamic mechanical and shape-memory properties of the polybenzoxazine are influenced by the combined effect of the cross-linking density and the ArF···HO hydrogen bonding. [ABSTRACT FROM AUTHOR]

Three peptides comprising mono-, di-, and tri-fluoroethylglycine (MfeGly, DfeGly, and TfeGly) residues alternating with lysine were digested by readily available proteases (elastase, bromelain, trypsin, and proteinase K). The degree of degradation depended on the enzyme employed and the extent of fluorination. Incubation of the peptides with a microbial consortium from garden soil resulted in degradation, yielding fluoride ions. Further biodegradation studies conducted with the individual fluorinated amino acids demonstrated that the degree of defluorination followed the sequence MfeGly > DfeGly > TfeGly. Enrichment of the soil bacteria employing MfeGly as a sole carbon and energy source resulted in the isolation of a bacterium, which was identified as Serratia liquefaciens . Cell-free extracts of this bacterium enzymatically defluorinated MfeGly, yielding fluoride ion and homoserine. In silico analysis of the genome revealed the presence of a gene that putatively codes for a dehalogenase. However, the low overall homology to known enzymes suggests a potentially new hydrolase that can degrade monofluorinated compounds. 19 F NMR analysis of aqueous soil extracts revealed the unexpected presence of trifluoroacetate, fluoride ion, and fluoroacetate. Growth of the soil consortium in tryptone soya broth supplemented with fluoride ions resulted in fluoroacetate production; thus, bacteria in the soil produce and degrade organofluorine compounds.

Activation of the C–F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bond-donating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bond-accepting ones are hindering it. However, the reaction is best run under highly concentrated conditions, where solvents cannot interfere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary amines or anilines to form benzylic amines in good yields.