Fluorination Reactions Research Articles

Protodefluorinated Selectfluor® Aggregatively Activates Selectfluor® for Efficient Radical C(sp3)-H Fluorination Reactions.

Efficient fluorination reactions are key in the late-stage functionalization of complex molecules in medicinal chemistry, in upgrading chemical feedstocks, and in materials science. Radical C(sp3)-H fluorinations using Selectfluor® - one of the most popular fluorination agents - allow to directly engage unactivated precursors under mild photochemical or thermal catalytic conditions. However, H-TEDA(BF4)2 to date is overlooked and discarded as waste, despite comprising 95% of the molecular weight of Selectfluor®. We demonstrate that the addition of H-TEDA(BF4)2 at the start of fluorination reactions markedly promotes their rates and accesses higher overall yields of fluorinated products (~3.3 × higher on average across the cases studied) than unpromoted reactions. Several case studies showcase generality of the promotor, for photochemical, photocatalytic and thermal radical fluorination reactions. Detailed mechanistic investigations reveal the key importance of aggregation changes in Selectfluor® and H-TEDA(BF4)2 to fill gaps of understanding in how radical C(sp3)-H fluorination reactions work. This study exemplifies an overlooked reaction waste product being upcycled for a useful application.

Reactivity tuning of metastable intermolecular composite Al/PFOA by polydopamine interfacial control

Controlling the high reactivity resulting from interfacial contact between nanoscale components poses a significant challenge. This study introduces an approach utilizing an aluminum (Al) surface-modified material to regulate the interaction between Al and perfluorooctanoic acid (PFOA), employing an in-situ synthesized polydopamine (PDA) interfacial layer. The optimal ratio was determined through molecular dynamics simulations. Various characterization techniques, including scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS), were employed to comprehensively analyze the structure and elemental distribution of the samples. The findings indicate that the PDA coating process did not alter the surface structure of Al while maintaining the integrity of the functional groups of both PDA and PFOA. Results from simultaneous thermal analysis (TG-DSC) demonstrate that the PDA interfacial layer increased the pre-ignition reaction (PIR) peak temperature of PFOA/Al by 2 °C and enhanced the heat release of the PIR and fluorination reaction by 1.3 and 34.8 times, respectively. Thermal analysis kinetics investigation revealed a reduction of 6.66 kJ⋅mol−1 in the activation energy of the fluorination reaction and an increase of 20.28 kJ⋅mol−1 in the activation energy of the PIR. Furthermore, the combustion heat and reaction degree of PFOA/Al@PDA powder increased by 43.4 % and approximately 8 %, respectively, compared to PFOA/Al powder generated by physical mixing. This study demonstrated that the inclusion of PDA modifiers in the PFOA/Al system effectively controls the exothermic reaction between fuel and oxidant and enhances the oxidation degree of Al.

Recent Advances in the Chemistry and Application of SF5-Compounds

AbstractThis review article outlines the literature from 2022 to 2024 covering developments in SF5 chemistry. Recent synthetic methodologies of SF5-containing building blocks are reported. These methods include the synthesis of SF5Cl and its use in pentafluorosulfanylation reactions and oxidative fluorination reactions. Moreover, the reactivity of SF5-alkynes as versatile platform to access new SF5-compounds is described. Finally, the effects of the SF5 moiety are highlighted according to its application in different fields, such as biological/medicinal chemistry, catalysis, and material sciences.1 Introduction2 Access to SF5-Containing Building Blocks2.1 By Means of SF5Cl2.1.1 Generation of SF5Cl2.2 By Means of Oxidative Fluorination2.3 By Means of SF5-Alkynes2.4 Other Miscellaneous Aromatic and Aliphatic SF5-Compounds3 Applications3.1 Medicinal and Biological Chemistry3.2 Material Science3.3 Catalysis4 Conclusion

Introduction of Fluorinated Groups via Photoredox-Catalyzed C–H Functionalization of (Hetero-)Arenes

AbstractIn recent years, there have been increasing efforts in the development of methodologies for incorporating fluorine-containing functional groups into organic scaffolds. Modern techniques have made fluorinated molecules more accessible than ever before, but many fluorination reactions still have limitations in their generality, predictability, sustainability, and cost-effectiveness. The methodological progress has a significant impact on drug discovery and materials science research. Photoredox catalysis has enabled the discovery of effective methods, providing access to druglike molecules. Photochemical methods paired with C–H functionalization provide powerful tools for property-driven research. Herein, we examine recent developments at the interface of photoredox catalysis and C–H functionalization.1 Introduction2 Fluorinations3 Fluoroalkylations4 Fluoroalkoxylations5 Conclusion

Pd-catalysed direct β-C(sp3)–H fluorination of aliphatic carboxylic acids

The ever-increasing demand for fluorinated molecules due to their widespread applications has raised substantial interest in the development of new synthetic methodologies that selectively introduce fluorine into molecular scaffolds. While transition-metal-catalysed fluorination reactions in principle provide a direct means to convert inert C–H bonds into C–F bonds, fundamental challenges such as the high energetic barriers associated with the formation of C–F bonds by reductive elimination, among others, remain to be systematically addressed. Carboxylic acids, owing to their versatile synthetic utility in organic synthesis, serve as ideal model substrates in this context. Here we report a protocol that enables the β-C(sp3)–H fluorination of free carboxylic acids, giving access to a wide range of fluorinated carboxylic acids. The rational design of the oxidizing reagent proved to be crucial in establishing the protocol and introduces an additional design dimension to the field of C–H activation.

Rhodium(III)-Catalyzed Annulation Synthesis of Difluorinated Quinazolinone Derivatives Using an Amide Carbonyl as the Directing Group.

The use of amide carbonyl groups of substrates as weakly coordinating directing groups has received a significant amount of attention. Recently, difluoromethylene alkynes have been successfully used in fluorination reactions, resulting in the preparation of various fluorine-containing compounds. This work describes a [4+2] annulation method for creating a range of fluorinated quinolino[2,1-b]quinazolinone derivatives. The derivatives are formed through Rh(III)-catalyzed cascade cyclization of 3-phenylquinazolinones and gem-difluoromethylene alkynes.

(Radio)Fluorination Reactions for the Synthesis of Aryl Fluorides: Recent Advances and Perspectives

The formation of carbon‐fluorine (C‐F) bonds is an important research field in organic synthesis because the insertion of a fluorine atom into an organic compound can alter its physicochemical properties, such as metabolic stability and permeability. Due to this unique property, organic fluorinated compounds, especially aryl fluorides, have a wide range of applications in various fields, including agrochemicals, pharmaceuticals, and materials science. Therefore, numerous metal‐ or metal‐free‐mediated fluorination reactions have been developed to synthesize aryl fluorides. In this mini‐review, we summarize recent ten years’ advances in fluorination reactions for the synthesis of aryl fluorides.

α-Fluorination of tropane compounds and its impact on physicochemical and ADME properties

Using an electrochemical C(sp3)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Nav1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold.

Fluorinated polymer-derived microporous carbon spheres for CFx cathodes with high energy density

Fluorinated carbon (CFx) compounds have extensive applications in lithium primary battery cathodes owing to their high energy density. In this investigation, a novel CFx compound offering superior electrochemical properties was synthesized via a low-temperature fluorination process, utilizing Pluronic F127 as a template agent and microporous carbon spheres produced through soft template-assisted high-temperature carbonization and chemical activation as precursors, and by regulating the amount of soft template F127 added. The reduction in microsphere size, narrower particle size distribution, and introduction of defects contribute to augmenting the molar ratio of F to C (F/C) of CFx while preserving the electrochemical activity of C-F bonds. The specific capacity of fluorinated polymer-derived microporous carbon spheres (FPMCSs) with a high fluorination degree rivals that of commercial fluorinated graphite (FG). The microsphere morphology and microporous structure not only furnish abundant sites for fluorination reactions in electrode processes but also facilitate Li+ diffusion, ensuring ample rate capability. The synthesized FPMCSs exhibited a peak specific capacity of 1079 mAh g–1 and a maximum energy density of 2679 Wh kg–1 (substantially surpassing the 2180 Wh kg–1 of commercial FG). Hence, the prepared FPMCSs underscore the significance of selecting suitable carbonaceous materials and designing structures deliberately, showing promising potential for achieving high energy density in CFx cathodes in the future, employing readily available and cost-effective raw materials.

Determination of the Hammett Acidity of HF/Base Reagents.

Harnessing the acidity of HF/base reagents is of paramount importance to improve the efficiency and selectivity of fluorination reactions. Yet, no general method has been reported to evaluate their acidic properties, and experimental designs are still relying on a trial-and-error approach. We report a new method based on 19F NMR spectroscopy which allows highly sensitive measures and short-time analyses. Advantageously, the basic properties of the indicators can be determined upstream by DFT calculations, affording a simple yet robust semiempirical approach. In particular, the indicators used in this study were rationally designed to fit on the conceptually appealing and commonly used Hammett scale. This method has been applied to commercially available and recently developed HF/base reagents.

Rocking-Chair Aqueous Fluoride-Ion Batteries Enabled by Hydrogen Bonding Competition.

Aqueous fluoride ion batteries (FIBs) have garnered attention for their high theoretical energy density, yet they are challenged by sluggish fluorination kinetics, active material dissolution, and electrolyte instability. Here, we present a room temperature rocking-chair aqueous FIBs featuring KOAc-KF binary salt electrolytes, enabling concurrent fluorination and defluorination reactions at both cathode and anode electrodes. Experimental and theoretical results reveal that acetate ions in the electrolyte compete with fluoride ions in hydrogen bonding formation, weakening the excessively strong solvation between H2O and F- ions. This results in the suppression of detrimental HF formation and a reduced desolvation energy of F- ions, enhancing the electrochemical reaction kinetics. The bismuth-based cathode exhibits direct conversion in the optimized electrolyte, effectively suppressing the detrimental disproportionation reactions from Bi2+ intermediates. Additionally, zinc anode undergoes a typical fluorination process, forming solid KZnF3 as the electrode product, minimizing the risks of hydrogen evolution. The proposed aqueous FIBs with the optimized electrolyte demonstrate high discharge capacity, long-term cycling stability and excellent rate capabilities.

Rocking‐Chair Aqueous Fluoride‐Ion Batteries Enabled by Hydrogen Bonding Competition

AbstractAqueous fluoride ion batteries (FIBs) have garnered attention for their high theoretical energy density, yet they are challenged by sluggish fluorination kinetics, active material dissolution, and electrolyte instability. Here, we present a room temperature rocking‐chair aqueous FIBs featuring KOAc‐KF binary salt electrolytes, enabling concurrent fluorination and defluorination reactions at both cathode and anode electrodes. Experimental and theoretical results reveal that acetate ions in the electrolyte compete with fluoride ions in hydrogen bonding formation, weakening the excessively strong solvation between H2O and F− ions. This results in the suppression of detrimental HF formation and a reduced desolvation energy of F− ions, enhancing the electrochemical reaction kinetics. The bismuth‐based cathode exhibits direct conversion in the optimized electrolyte, effectively suppressing the detrimental disproportionation reactions from Bi2+ intermediates. Additionally, zinc anode undergoes a typical fluorination process, forming solid KZnF3 as the electrode product, minimizing the risks of hydrogen evolution. The proposed aqueous FIBs with the optimized electrolyte demonstrate high discharge capacity, long‐term cycling stability and excellent rate capabilities.

Highly energetic formulations of boron and polytetrafluoroethylene for improved ignition and oxidative heat release

Boron (B) is desirable for energetic applications due to high gravimetric and volumetric energy densities. However, their use is limited because the native oxide shells on their surfaces limit oxidation and heat release by acting as a diffusion barrier and dead weight that does not contribute to heat release during oxidation. This paper reports a facile and efficient method of blending B with perfluoro additives to obtain materials with augmented heat release. We use polytetrafluoroethylene (PTFE) as a fluorine source that reacts with the oxide layer exothermally and use thermochemical analysis to identify the optimum composition of PTFE to extract high energy from B as a result of synergistic oxidation and fluorination reactions. The reduction in ignition temperatures of B is also observed due to its blending with PTFE. In this work, we determined B/PTFE blends with lower ignition temperature and higher oxidative heat release. These effects are due to the gasification of native surface oxide by fluorine via exothermic reactions that facilitate the enhanced reactions in the exposed metal core by eliminating the kinetic/thermodynamic barrier in the diffusion of the oxidizer to the B particle core. The study demonstrates the optimized formulation of highly energetic blends of B/PTFE for energetic applications.

Development of direct C-3 difluoromethylation reaction for application in synthesis of quinoline-related drugs

Fluorine holds a prominent position within the realm of drug discovery and development, substantiated by its presence in approximately 25% of drugs approved by the US Food and Drug Administration (FDA). Consequently, the advancement of new fluorination reactions stands as a pivotal area in medicinal chemistry. In particular, the monofluoro-, difluoromethyl-, and trifluoromethyl- are three groups that appear most frequently in drug structure. Quinoline, owing to its privileged structural status, plays a crucial role in drug design and synthesis. Various approaches have been documented for the direct difluoromethylation of the C-2 and C-4 positions of the quinoline ring. However, achieving direct C-3 difluoromethylation has remained an elusive objective. In this study, we introduce a novel method for effecting the direct difluoromethylation at the C-3 position of the quinoline ring.Comprehensive characterizations, including 1H-NMR, 13C-NMR, and 19F-NMR for all compounds are performed. We believe that this novel method will open a new way to access the hitherto untapped C-3-difluoromethylation active compounds.

Where do the Fluorine Atoms Go in Inorganic‐Oxide Fluorinations? A Fluorooxoborate Illustration under Terahertz Light

AbstractThe substitution of fluorine atoms for oxygen atoms/hydroxyl groups has emerged as a promising strategy to enhance the physical and chemical properties of oxides/hydroxides in fluorine chemistry. However, distinguishing fluorine from oxygen/hydroxyl in the reaction products poses a significant challenge in existing characterization methods. In this study, we illustrate that terahertz (THz) spectroscopy provides a powerful tool for addressing this challenge. To this end, we investigated two fluorination reactions of boric acid, utilizing MHF2 (M=Na, C(NH2)3) as fluorine reagents. Through an interplay between THz spectroscopy and solid‐state density functional theory, we have conclusively demonstrated that fluorine atoms exclusively bind with the sp3‐boron but not with the sp2‐boron in the reaction products of Na[B(OH)3][B3O3F2(OH)2] (NaBOFH) and [C(NH2)3]2B3O3F4OH (GBF2). Based on this evidence, we have proposed a reaction pathway for the fluorinations under investigation, a process previously hindered due to structural ambiguity. This work represents a step forward in gaining a deeper understanding of the precise structures and reaction mechanisms involved in the fluorination of oxides/hydroxides, illuminated by the insights provided by THz spectroscopy.

Where do the Fluorine Atoms Go in Inorganic-Oxide Fluorinations? A Fluorooxoborate Illustration under Terahertz Light.

The substitution of fluorine atoms for oxygen atoms/hydroxyl groups has emerged as a promising strategy to enhance the physical and chemical properties of oxides/hydroxides in fluorine chemistry. However, distinguishing fluorine from oxygen/hydroxyl in the reaction products poses a significant challenge in existing characterization methods. In this study, we illustrate that terahertz (THz) spectroscopy provides a powerful tool for addressing this challenge. To this end, we investigated two fluorination reactions of boric acid, utilizing MHF2 (M=Na, C(NH2)3) as fluorine reagents. Through an interplay between THz spectroscopy and solid-state density functional theory, we have conclusively demonstrated that fluorine atoms exclusively bind with the sp3-boron but not with the sp2-boron in the reaction products of Na[B(OH)3][B3O3F2(OH)2] (NaBOFH) and [C(NH2)3]2B3O3F4OH (GBF2). Based on this evidence, we have proposed a reaction pathway for the fluorinations under investigation, a process previously hindered due to structural ambiguity. This work represents a step forward in gaining a deeper understanding of the precise structures and reaction mechanisms involved in the fluorination of oxides/hydroxides, illuminated by the insights provided by THz spectroscopy.

Activation of fluoride anion as nucleophile in water with data-guided surfactant selection.

A principal component surfactant_map was developed for 91 commonly accessible surfactants for use in surfactant-enabled organic reactions in water, an important approach for sustainable chemical processes. This map was built using 22 experimental and theoretical descriptors relevant to the physicochemical nature of these surfactant-enabled reactions, and advanced principal component analysis algorithms. It is comprised of all classes of surfactants, i.e. cationic, anionic, zwitterionic and neutral surfactants, including designer surfactants. The value of this surfactant_map was demonstrated in activating simple inorganic fluoride salts as effective nucleophiles in water, with the right surfactant. This led to the rapid development (screening 13-15 surfactants) of two fluorination reactions for β-bromosulfides and sulfonyl chlorides in water. The latter was demonstrated in generating a sulfonyl fluoride with sufficient purity for direct use in labelling of chymotrypsin, under physiological conditions.

Synthesis of fluorinated spiro-1,3-oxazines and thiazines via Selectfluor-mediated intramolecular cyclization.

A fluorination-induced intramolecular cyclization for the synthesis of fluoro-substituted spiro-1,3-oxazine and spiro-1,3-thiazine derivatives is described. N-(2-(Cyclohex-1-en-1-yl)ethyl)benzamide and benzothioamide are used as the substrates, and the cationic fluorinating agent Selectfluor works as the fluoride source. The reaction yields a single diastereomer. The scope of this regioselective fluorination reaction is established by preparing thirty different spirooxazine and spirothiazine derivatives.

Radical fluorine transfer catalysed by an engineered nonheme iron enzyme.

Nonheme iron enzymes stand out as one of the most versatile biocatalysts for molecular functionalization. They facilitate a wide array of chemical transformations within biological processes, including hydroxylation, chlorination, epimerization, desaturation, cyclization, and more. Beyond their native biological functions, these enzymes possess substantial potential as powerful biocatalytic platforms for achieving abiological metal-catalyzed reactions, owing to their functional and structural diversity and high evolvability. To this end, our group has recently engineered a series of nonheme iron enzymes to employ non-natural radical-relay mechanisms for abiological radical transformations not previously known in biology. Notably, we have demonstrated that a nonheme iron enzyme, (S)-2-hydroxypropylphosphonate epoxidase from Streptomyces viridochromogenes (SvHppE), can be repurposed into an efficient and selective biocatalyst for radical fluorine transfer reactions. This marks the first known instance of a redox enzymatic process for C(sp3)F bond formation. This chapter outlines the detailed experimental protocol for engineering SvHPPE for fluorination reactions. Furthermore, the provided protocol could serve as a general guideline that might facilitate other engineering endeavors targeting nonheme iron enzymes for novel catalytic functions.

Metal Ion-Induced Large Fragment Deactivation: A Different Strategy for Site-Selectivity in a Complex Molecule.

Complex natural product functionalizations generally involve the use of highly engineered reagents, catalysts, or enzymes to react exclusively at a desired site through lowering of a select transition state energy. In this communication, we report a new, complementary strategy in which all transition states representing undesirable sites in a complex ionophore substrate are simultaneously energetically increased through the chelation of a metal ion to the large fragment we wish to neutralize. In the case of an electrophilic, radical based fluorination reaction, charge repulsion (electric field effects), induced steric effects, and electron withdrawal provide the necessary deactivation and proof of principle to afford a highly desirable natural product derivative. We envisage that many other electrophilic or charge based synthetic methods may be amenable to this approach as well.