Fluorine-containing Molecules Research Articles

Effect of Fluorine Substitution on Magnetizabilities: Insights from Density Functional Theory and Benchmark Coupled-Cluster Calculations.

The quantitative calculation of the magnetizability tensor of fluorine-containing molecules has been a longstanding challenge for quantum chemistry. We report a benchmark study on the effect of fluorine substitution on the magnetizability (both isotropic and anisotropic) of 24 small closed-shell molecules using coupled-cluster (CCSD(T)) theory, large basis sets, and London atomic orbitals. By extrapolation to a complete basis set (CBS) result, we establish the CCSD(T)/CBS limit and take the opportunity to assess the performance of various density functional theory approximations. Correcting for zero-point vibration further allows us to directly compare theory with (gas-phase) experimental data. We revisit Flygare's hypothesis on molecular magnetizabilities, which relates the successive replacement of hydrogen by fluorine atoms to changes in the magnetizability anisotropy. Some exceptions to this hypothesis are documented, and we rationalize these observations on the basis of hybridization on carbon.

Making Full Use of TMSCF3: Deoxygenative Trifluoromethylation/Silylation of Amides.

As one of the most powerful trifluoromethylation reagents, (trifluoromethyl)trimethylsilane (TMSCF3) has been widely used for the synthesis of fluorine-containing molecules. However, to the best of our knowledge, the simultaneous incorporation of both TMS- and CF3- groups of this reagent onto the same carbon of the products has not been realized. Herein, we report an unprecedented SmI2/Sm promoted deoxygenative difunctionalization of amides with TMSCF3, in which both silyl and trifluoromethyl groups are incorporated into the final product, yielding α-silyl-α-trifluoromethyl amines with high efficiency. Notably, the silyl group could be further transformed into other functional groups, providing a new method for the synthesis of α-quaternary α-CF3-amines.

Functional energetic materials: Simple preparation of fluorinated materials to improve safety, preservation and energy release performance of energetic materials

Paraffin wax (PW) coatings are widely used in the military as the most effective way to reduce the sensitivity of energetic materials, but their inert nature is not conducive to energy release. In this work, paraffin-like fluorine-containing molecules (FPW) which are highly anticipated on a large scale were synthesized by combining crystalline units with fluorine units via a simple method. Core-shell Al@FPW was prepared for further characterization. FPW exhibits better lubrication and greater density (1.14 g/cm3 vs. 0.81 g/cm3) than PW, which can provide favorable guarantees for reduced friction sensitivity and increased energy density. The similar melting temperatures and crystallization enthalpies (168 J/g vs. 201 J/g) of FPW and PW are advantageous for mitigating the temperature sensitivity of nano-Al. Furthermore, the improved hydrophobicity of Al@FPW prevents further oxidation of the active metal, thereby enhancing the preservation of nano-Al. Moreover, the reaction process of Al@FPW was characterized by DSC-Tg. Notably, the combustion pressure, pressurization rate and calorific value of Al@FPW are significantly increased compared to Al@PW. Meanwhile, the ignition delay time is reduced by 83 % and the combustion rate is increased by 330 %, which is attributed to the action of fluorine during the reaction. The exceptional performance of FPW holds great potential for replacing PW in various applications.

The Pharmaceutical Industry in 2023: An Analysis of FDA Drug Approvals from the Perspective of Molecules.

With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody-drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year's harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.

Fluorinated Iron Metal-Organic Frameworks for Activatable 19F Magnetic Resonance Imaging and Synergistic Therapy of Tumors.

Due to their appealing physiochemical properties, metal-organic frameworks (MOFs) have been widely employed in biomedical fields. In this study, we utilize ferric ions and fluorine-containing organic ligands as both structural and functional units to develop a stimulus-responsive nanoagent, 19FIMOF-TA nanoparticles, for activatable 19F magnetic resonance imaging (MRI) and synergistic therapy of tumors. This nanoagent could respond to excess GSH in a tumor microenvironment, discharging fluorinated organic ligands and reduced ferrous ions. The release of these fluorine-containing small molecules results in boosting of the 19F MRI signals, which could be further enhanced by the photothermal effect of this nanoagent to achieve a responsive cascaded amplification of 19F MRI signals for tumor visualization. Meanwhile, ferroptosis promoted by the ferrous ions leads to significant tumor cell death, which is synergistically aggravated by the photothermal effect. The encouraging results illustrate the promising potential of our nanoagent for effective tumor imaging and combinative cancer therapy.

First-principles study on adsorption behaviors of fluorine-containing gases on pure, Co- and Pd-doped Ag(111) surfaces

Based on density functional theory (DFT), the adsorption processes of fluorine-containing gases (F2, hydrogen fluoride (HF), and SOF2) on pure, Co- and Pd-doped Ag(111) surfaces were investigated by first-principles calculation. It is found that three fluorine-containing gases exhibit different adsorption behaviors on different adsorption surfaces. Co-doped Ag(111) surfaces show both physical adsorption and chemisorption, while Ag(111) surfaces and Pd-doped Ag(111) surfaces show chemisorption. Co doping and Pd doping on the Ag(111) surface greatly improves the adsorption properties of adsorbents for F2 and SOF2 gas molecules. Results of electron orbital and charge density difference analyses show that hybridization occurs between fluorine-containing gas molecules and adsorbents during the adsorption process. It results in new chemical bond formation and eventually leads to different adsorption behaviors. The F2_F–Co site is the optimal adsorption site for the F2 molecule, and its charge transfer amount is the largest as well. Co doping and Pd doping have little effect on the adsorption of HF molecules, and HF molecules tend to be preferentially adsorbed at the HF_H–Ag site. The adsorption behavior of SOF2 molecules on different surfaces is different from that of the above two gas molecules. The SOF2 molecule tends to adsorb around the Pd atom, and the O atom is closer to the adsorbent.

Fluoroalkylation of Activated Allylic Acetates through Radical-Radical Coupling: Organophotoredox/DABCO Catalytic System.

A novel organophotoredox/DABCO catalytic system for the fluoroalkylation of activated allylic acetates via radical-radical coupling is described. The method offers mild reaction conditions, high selectivity, and broad substrate compatibility and enabled diverse bioactive molecules, FDA-approved drugs, and amino acid derivatives to be incorporated into transformation. This study expands the synthetic toolbox for the construction of fluorine-containing molecules.

Rapid Measurement of Heteronuclear Coupling Constants in Complex NMR Spectra.

The NMR analysis of fluorine-containing molecules, increasingly widespread due to their importance in pharmaceuticals and biochemistry, poses significant challenges. Severe peak overlap in the proton spectrum often hinders the extraction of critical structural information in the form of heteronuclear scalar coupling constants, which are crucial for determining pharmaceutical properties and biological activity. Here, a new method, IPAP-FESTA, is reported that drastically simplifies measurements of the signs and magnitudes of proton-fluorine couplings. Its usefulness is demonstrated for the structural study of the steroidal drug fluticasone propionate extracted from a commercial formulation and for assessing solvent effects on the conformational equilibrium in a physically inseparable fluorohydrin mixture.

Differentiation of Superoxide Radical Anion and Singlet Oxygen and Their Concurrent Quantifications by Nuclear Magnetic Resonance.

While there have been various techniques, assays, and commercial kits developed to measure reactive oxygen species (ROS) with varying degrees of success, there is a lack of innovative methods to differentiate and quantify them simultaneously. In this work, we demonstrate a 19F nuclear magnetic resonance (NMR)-based method to differentiate two important types of ROS, superoxide radical anion and singlet oxygen, and to quantify them concurrently. By taking advantage of the unique chemical reactivity of two fluorine-containing molecules, 4-fluoro-3-methylphenyl boronic acid and 4-fluoro-3-methylphenol, serving as 19F NMR probes, we are able to differentiate and quantify, for the first time, superoxide radical anion and singlet oxygen generated by photosensitizers (PSs) concurrently. The results reveal that relative amounts of superoxide radical anion and singlet oxygen generated by a PS under light illumination are oftentimes sensitive to the environment, such as the presence or absence of electron donors. This method provides a means to identify the type of mechanism by which a PS functions under a given condition. We envision that this relatively simple, yet robust, method would be beneficial to a broad range of ROS-pertinent studies, such as photodynamic therapy and photoredox reactions.

Carbotrifluoromethylations of C-C Multiple Bonds (Excluding Aryl- and Alkynyltrifluoromethylations).

Organofluorine chemistry has become an expanding area of research in organic chemistry and drug design. The synthesis of fluorine-containing molecules has received high significance in synthetic chemistry. Trifluoromethylative difunctionalizations of carbon-carbon multiple bonds with the simultaneous introduction of a CF3 group and another function have considerable relevance. Because of the high importance of carbon-carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations are considered to be a field of synthetic chemistry of increasing importance. Our current goal in this review is to summarize recent developments of various trifluoromethylation reactions (excluding aryl- and alkynyl-trifluoromethylations) taking into consideration several main approaches, such as alkenyltrifluoromethylation, alkyltrifluoromethylation, carbonyltrifluoromethylation, and cyanotrifluoromethylation reactions.

Superhydrophobic and Durable Silver-Coated Fabrics for Efficient Electromagnetic Interference Shielding

Superhydrophobic surfaces present promising potential for improving the mechanical and chemical durability of electromagnetic interference (EMI) shielding materials. However, integrating superhydrophobicity and EMI shielding is still a challenge due to the complex structural design. Herein, superhydrophobic and highly durable fabrics with excellent EMI shielding effectiveness were fabricated. First, the meta-aramid nonwoven fabrics were functionalized by a polydopamine layer. Then, with the assistance of the metal-binding ability of polydopamine, silver nanoparticles were immobilized on the fiber surface by electroless plating. Finally, after the introduction of fluorine-containing agents via a facile dipping method, a superhydrophobic surface was successfully obtained. The as-prepared fabrics showed excellent EMI shielding effectiveness of 111 dB due to superior electrical conductivity (234 S/cm). Moreover, thanks to the low surface energy of fluorine-containing molecules as well as the micro-nanoroughness created by the stacking of silver nanoparticles, the composite fabrics exhibited a large water contact angle of 152° and a low sliding angle of 5°. It was noted that the composite fabrics still maintain superhydrophobicity and high EMI shielding effectiveness (110 dB) even after the acid and alkali corrosion, bending, abrading, and salt fog test, respectively, demonstrating their durability under harsh environments.

The Pharmaceutical Industry in 2022: An Analysis of FDA Drug Approvals from the Perspective of Molecules.

While 2021 ended with the world engulfed in the COVID-19 Omicron wave, 2022 has ended in almost all countries, except China, with COVID-19 being likened to the flu. In this context, the U.S. Food and Drug Administration (FDA) has authorized only 37 new drugs this year compared to an average of 52 in the last four years. Thus 2022 is the second lowest harvest after 2016 in the last six years. This ranking may be transient and will be confirmed in the coming years. In this regard, the reduction in the number of drugs accepted by the FDA this year applies only to the so-called small molecules as there has been no variation in the respective numbers of biologics or TIDES (peptides and oligonucleotides). Monoclonal antibodies (mAbs) continue to be the class with the most drugs authorized (9), while proteins/enzymes (5) and an antibody-drug conjugate complete the biologics harvest. In 2022, five TIDES and seven drugs inspired by natural products have received the green light, thus showing the same tendency as in previous years. Finally, pharmaceutical agents with nitrogen aromatic heterocycles and/or fluorine atoms continue to be predominant among small molecules this year. Furthermore, three drugs have been approved for imaging, reinforcing the trend in recent years for this class of treatments. A keyword in 2022 is bispecificity since four drugs have this property (two mAbs, one protein, and one peptide). Herein, the 37 new drugs approved by the FDA in 2022 are analyzed. On the basis of chemical structure alone, these drugs are classified as the following: biologics (antibodies, antibody-drug conjugates, proteins/enzymes), TIDES (peptide and oligonucleotides), combined drugs, natural products; nitrogen aromatic heterocycles, fluorine-containing molecules, and other small molecules.

Ring-Opening Fluorination of Carbo/Heterocycles and Aromatics: Construction of Complex and Diverse Fluorine-Containing Molecules.

Fluorine-containing molecules have attracted much attention in medicinal, agrochemical, and materials sciences because they offer unique physical and biological properties. Therefore, many efficient fluorination reactions have been developed over the years. Recent advancements in fluorination chemistry have expanded the range of substrates, and regioselectivity/stereoselectivity control has also been achieved. Ring-opening fluorination is an efficient method to construct complex fluorine-containing molecules with diversity, starting from simple cyclic compounds. This review aims to summarize developments in ring-opening fluorination, particularly with larger-sized cyclic compounds. Fluorine introduction and bond cleavage of cyclic compounds such as carbocycles, heterocycles, and aromatics provide efficient access to fluorine-containing compounds that are difficult to be synthesized by conventional methods.

Multifunctional Superamphiphobic Cotton Fabrics with Highly Efficient Flame Retardancy, Self-Cleaning, and Electromagnetic Interference Shielding

Here, a facile method is reported to prepare multifunctional cotton fabrics with high flame retardancy, high electrical conductivity, superamphiphobicity, and high electromagnetic shielding. The cotton fabric surface was first modified with phytic acid (PA), which promoted dehydration and carbonization of cellulose to increase flame retardancy in the process of pyrolysis. Tannic acid (TA) and 3-aminopropyltriethoxysilane (APTES) coating with nanospheres as interlayers created hierarchical roughness that facilitated the construction of superamphiphobic surfaces and provided adhesion sites for silver nanoparticles. In addition, the TA-APTES coating improved flame retardancy because the APTES-containing silicon could form silicon carbon layers to isolate heat and oxygen. Subsequently, the surface energy of the composite cotton fabric was reduced by fluorine-containing molecules. The prepared composite cotton fabric exhibited excellent superamphiphobicity with contact angles of 160.3 and 152° for water and olive oil, respectively. The conductivity and EMI shielding efficiency of the prepared composite cotton fabric reached 629.93 S/cm and 76 dB, respectively. Importantly, the composite cotton fabric maintained a relatively stable EMI shielding efficiency even after cyclic bending and abrasion tests. Moreover, the composite cotton fabric possessed a high limiting oxygen index (LOI) of 45.3% and self-extinguishing properties with the peak heat release rate (PHHR) and total heat release (THR) reduced by 73 and 67%, respectively, than the pure cotton fabric, indicating the outstanding flame retardancy.

Organophotoredox-catalyzed ring-opening gem-difluoroallylation of nonstrained cycloalkanols

Gem-difluoroalkenes exhibit widespread applications in pharmaceuticals, pesticides, and materials, and also serve as versatile building blocks for the synthesis of fluorine-containing molecules. In this report, we present a visible-light-promoted metal-free protocol for the regiospecific construction of distally unsaturated ketones bearing both versatile ketone and gem-difluoroalkene moieties. A wide range of distal gem-difluoroalkenyl ketones were readily obtained in good yields by the organophotocatalytic ring-opening defluorinative gem-difluoroallylation of nonstrained cycloalkanols with α-trifluoromethyl alkenes. This transformation exhibits broad functional group compatibility and occurs under mild, metal-free, and redox-neutral conditions. Mechanistic studies disclose that the reaction proceeds through sequential intramolecular PCET, ring opening C–C bond scission, radical-polar crossover, and E1cB fluoride elimination processes.

Ab-initio molecular dynamics simulations of the reactivity of MoS2 towards F2 molecules: Implications for etching processes

We investigated the reactivity of fluorinated monolayer and bilayer MoS2 in relation to etching processes. We considered both the energetics and the dynamics of the different processes: a) interaction of fluorine species in the gas phase with MoS2, b) the surface chemistry of SF, SF2, and SF3 groups and c) the desorption of fluorine-containing molecules into the gas phase. The dissociative adsorption of F2 occurs at very low temperatures (100 K) and the surface becomes populated by SF, SF2 (the most stable), and SF3 groups. Etching processes begin with the desorption of the SF3 group and only at very high temperatures the desorption of SF2 was observed. Sulfur vacancies left by the removal of S atoms are rapidly filled by F atoms due to the formation of strong MoF bonds. The formation of a sulfur vacancy induces the subsequent formation of S-vacancies on adjacent surface sites, and this finally promotes the desorption of MoF5 or MoF6 species, thus leaving a surface pit defect. For a MoS2 bilayer with the top layer fluorinated on both sides, the etching of the top layer was observed as a consequence of the release of SFx species within the interlayer region.

Fluoro Hydrogen Peroxide: A Plausible Molecular Form of Naturally-Occurring Fluorine

Fluorine’s hostile nucleosynthetic environment makes it one of the least common elements and, consequently, understudied both on the earth and in the interstellar medium (ISM). However, the presence of fluorine-containing species in both the ISM and in the earth’s atmosphere necessitates the existence of a pathway out of this environment to form fluorine-containing molecules. To that end, the presence of fluorine and hydroperoxyl radical (HO2) in either of these environments may lead to the formation of fluorinated molecules like fluoro hydrogen peroxide (HOOF) on dust grains of protoplanetary disks in the planet-forming regions of ρ Oph and in the earth’s atmosphere as a sink for other fluorine pollutants that have yet to be detected. This theoretical study utilizes explicitly correlated coupled cluster theory computed with core correlation and corrections from scalar relativity to provide the first anharmonic fundamental vibrational frequencies and rotational constants of HOOF for use as reference benchmarking of further computational or experimental study, as well as potential astrophysical observation. The ν6 bending frequency for HOOF at 454.4 cm–1 exhibits an anharmonic transition intensity of 78 km/mol, while the ν4 frequency at 738.2 cm–1 is 66 km/mol. Additionally, HOOF has a large net dipole moment of 2.12 D compared to the previously detected HF and HOOH molecules, 1.82 and 1.85 D, respectively, resulting from the electronegativity of the fluorine. Consequently, HOOF is a likely candidate for possible detection via vibrational and rotational spectroscopy to further the understanding of fluorine’s small, but important, role in astrochemical and atmospheric environments.

Erratum: “Density functional theory study on the fluorination reactions of silicon and silicon dioxide surfaces using different fluorine-containing molecules” [J. Vac. Sci. Technol. A 37, 021001 (2019)

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Recent Progress in Aryltrifluoromethylation Reactions of Carbon-Carbon Multiple Bonds.

Due to the increasing relevance of fluorine-containing organic molecules in drug design, the synthesis of organofluorine compounds has gained high significance in synthetic organic chemistry. Trifluoromethylative difunctionalizations of carbon-carbon multiple bonds, with the simultaneous incorporation of a CF3 group and another functional element, have considerable potential. Because of the high importance of carbon-carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations and, in particular, aryltrifluoromethylations or heteroaryltrifluoromethylations are considered to be increasing fields of synthetic organic chemistry. The aim of the current review is to summarize recent developments of aryltrifluoromethylation or heteroaryltrifluoromethylation reactions.

Developments in the Alkynyltrifluoromethylations of Alkenes and Alkynes

AbstractAs a consequence of the expanding relevance of fluorine-containing organic molecules in drug research, the synthesis of organofluorine scaffolds has high significance in synthetic organic chemistry. Trifluoromethylative difunctionalizations of carbon–carbon multiple bonds, with the simultaneous introduction of a CF3 group and another function, have considerable potential. Considering the high importance of carbon–carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations and, in particular, alkynyltrifluoromethylations have increasing interest in synthetic chemistry. Alkynyltrifluoromethylation is a narrow area and a relatively new approach in synthetic chemistry­; however it has not been reviewed so far. Our goal in this short review is to summarize recent developments in alkynyltrifluoromethylation reactions by considering: (a) alkynyltrifluoromethylation reactions of alkenes, including reactions involving either intramolecular alkynyl migration or intermolecular transformation, and (b) alkynyltrifluoromethylation reactions of alkynes.1 Introduction2 Alkynyltrifluoromethylation Reactions of Alkenes2.1 Reactions Involving Intramolecular Alkynyl Migration2.2 Intermolecular Reactions3 Alkynyltrifluoromethylation Reactions of Alkynes4 Summary and Outlook