Synthesis of gem-Difluorinated 2,3-Dihydrobenzofurans Using Freon-22 via [4 + 1] Annulation of Difluorocarbene and Antitumor Activity Evaluation.

As an inexpensive industrial chemical, chlorodifluoromethane (Freon-22), despite its relatively low reactivity, can serve as a practical CF2 source for the construction of gem-difluorinated ring structures. Here, we develop a protocol for the efficient assembly of valuable fluorinated 2,3-dihydrobenzofurans from the [4 + 1] annulation in good yields under basic conditions. The reliable practicability and scalability of the process have also been demonstrated by preparation at the multigram scale, late-stage modifications of pharmaceutical molecules, and potential antitumor potency.

Catalytic hydrolysis of monochlorodifluoromethane over ZnO/ZrO2 catalysts at low temperatures.

Monochlorodifluoromethane (HCFC-22) has been identified as a significant contributor to the depletion of the Earth's ozone layer, garnering considerable attention within the scientific community. Consequently, the investigation of Freon degradation has become a central focus of current research efforts. In this study, we opted to employ catalytic hydrolysis as it offers numerous advantages for the degradation of HCFC-22. Specifically, we prepared ZnO/ZrO2 catalysts with hexahedral rod-like structures through citric acid complexation. We examined the impact of various preparation conditions (such as the molar ratio of ZnO to ZrO2, calcination temperature, and calcination time) as well as catalytic hydrolysis conditions (including the amount of catalyst, total flow rate, and catalytic hydrolysis temperature) on the hydrolysis rate of HCFC-22. Characterization of the catalysts was performed using techniques such as XRD, SEM, EDS, TG-DTG, FTIR, N2 adsorption-desorption, CO2-TPD, and NH3-TPD. Our experimental findings revealed the optimal preparation conditions: a catalytic hydrolysis temperature of 100 °C, a molar ratio of ZnO to ZrO2 of 0.7, a water bath temperature of 90 °C, a roasting temperature of 400 °C, and a roasting time of 4 h. At a catalytic hydrolysis temperature of 100 °C, the hydrolysis rate of HCFC-22 reached 99.81%, with the main hydrolyzed products being HCl, HF, and CO2.

Hydrodehalogenation of Trichlorofluoromethane over Biogenic Palladium Nanoparticles in Ambient Conditions.

Among a number of persistent chlorofluorocarbons (CFCs, or freons), the emissions of trichlorofluoromethane (CFCl3, CFC-11) have been increasing since 2002. Zero-valent-Pd (Pd0) catalysts are known to hydrodehalogenate CFCs; however, most studies rely on cost-inefficient and eco-unfriendly chemical synthesis of Pd0NPs and harsh reaction conditions. In this study, we synthesized Pd0 nanoparticles (Pd0NPs) using D. vulgaris biomass as the support and evaluated hydrodehalogenation of CFC-11 catalyzed by the biogenic Pd0NPs. The presence of D. vulgaris biomass stabilized and dispersed 3-6 nm Pd0NPs that were highly active. We documented, for the first time, Pd0-catalyzed simultaneous hydrodechlorination and hydrodefluorination of CFC-11 at ambient conditions (room temperature and 1 atm). More than 70% CFC-11 removal was achieved within 15 h with a catalytic activity of 1.5 L/g-Pd/h, dechlorination was 50%, defluorination was 41%, and selectivity to fully dehalogenated methane was >30%. The reaction pathway had a mixture of parallel and sequential hydrodehalogenation. In particular, hydrodefluorination was favored by higher H2 availability and Pd0:CFC-11 ratio. This study offers a promising strategy for efficient and sustainable treatment of freon-contaminated water.

Difluoromethylation of Unactivated Alkenes Using Freon-22 through Tertiary Amine-Borane-Triggered Halogen Atom Transfer.

The application of abundant and inexpensive fluorine feedstock sources to synthesize fluorinated compounds is an appealing yet underexplored strategy. Here, we report a photocatalytic radical hydrodifluoromethylation of unactivated alkenes with an inexpensive industrial chemical, chlorodifluoromethane (ClCF2H, Freon-22). This protocol is realized by merging tertiary amine-ligated boryl radical-induced halogen atom transfer (XAT) with organophotoredox catalysis under blue light irradiation. A broad scope of readily accessible alkenes featuring a variety of functional groups and drug and natural product moieties could be selectively difluoromethylated with good efficiency in a metal-free manner. Combined experimental and computational studies suggest that the key XAT process of ClCF2H is both thermodynamically and kinetically favored over the hydrogen atom transfer pathway owing to the formation of a strong boron-chlorine (B-Cl) bond and the low-lying antibonding orbital of the carbon-chlorine (C-Cl) bond.

Levels and Seasonal Trends of C1-C4 Perfluoroalkyl Acids and the Discovery of Trifluoromethane Sulfonic Acid in Surface Snow in the Arctic.

C1-C4 perfluoroalkyl acids (PFAAs) are highly persistent chemicals that have been found in the environment. To date, much uncertainty still exists about their sources and fate. The importance of the atmospheric degradation of volatile precursors to C1-C4 PFAAs were investigated by studying their distribution and seasonal variation in remote Arctic locations. C1-C4 PFAAs were measured in surface snow on the island of Spitsbergen in the Norwegian Arctic during January-August 2019. Trifluoroacetic acid (TFA), perfluoropropanoic acid (PFPrA), perfluorobutanoic acid (PFBA), and trifluoromethane sulfonic acid (TFMS) were detected in most samples, including samples collected at locations presumably receiving PFAA input solely from long-range processes. The flux of TFA, PFPrA, PFBA, and TFMS per precipitation event was in the ranges of 22-1800, 0.79-16, 0.19-170, and 1.5-57 ng/m2, respectively. A positive correlation between the flux of TFA, PFPrA, and PFBA with downward short-wave solar radiation was observed. No correlation was observed between the flux of TFMS and solar radiation. These findings suggest that atmospheric transport of volatile precursors and their subsequent degradation plays a major role in the global distribution of C2-C4 perfluoroalkyl carboxylic acids and their consequential deposition in Arctic environments. The discovery of TFMS in surface snow at these remote Arctic locations suggests that TFMS is globally distributed. However, the transport mechanism to the Arctic environment remains unknown.

Inability of GSTT1 to activate iodinated halomethanes to mutagens in Salmonella.

Drinking water disinfection by-products (DBPs), including the ubiquitous trihalomethanes (THMs), are formed during the treatment of water with disinfectants (e.g., chlorine, chloramines) to produce and distribute potable water. Brominated THMs (Br-THMs) are activated to mutagens via glutathione S-transferase theta 1 (GSTT1); however, iodinated THMs (I-THMs) have never been evaluated for activation by GSTT1. Among the I-THMs, only triiodomethane (iodoform) has been tested previously for mutagenicity in Salmonella and was positive (in the absence of GSTT1) in three strains (TA98, TA100, and BA13), all of which have error-prone DNA repair (pKM101). We evaluated five I-THMs (chlorodiiodomethane, dichloroiodomethane, dibromoiodomethane, bromochloroiodomethane, and triiodomethane) for mutagenicity in Salmonella strain RSJ100, which expresses GSTT1, and its homologue TPT100, which does not; neither strain has pKM101. We also evaluated chlorodiiodo-, dichloroiodo-, and dibromoiodo-methanes in strain TA100 +/- rat liver S9 mix; TA100 has pKM101. None was mutagenic in any of the strains. The I-THMs were generally more cytotoxic than their brominated and chlorinated analogues but less cytotoxic than analogous trihalonitromethanes tested previously. All five I-THMs showed similar thresholds for cytotoxicity at ~2.5 µmoles/plate, possibly due to release of iodine, a well-known antimicrobial. Although none of these I-THMs was activated by GSTT1, iodoform appears to be the only I-THM that is mutagenic in Salmonella, only in strains deficient in nucleotide excision repair (uvrB) and having pKM101. Given that only iodoform is mutagenic among the I-THMs and is generally present at low concentrations in drinking water, the I-THMs likely play little role in the mutagenicity of drinking water.

Trifluoromethanesulfonamide vs. Non-Fluorinated Sulfonamides in Oxidative Sulfamidation of the C=C Bond: An In Silico Study.

A theoretical analysis of the reaction of oxidative sulfamidation of several alkenes was performed in order to explain the various experimental observations and different reactivity of triflamide and non-fluorinated sulfonamides. Transformations occurring in the system alkene-sulfonamide in the presence of oxidative system (ButOCl + NaI) were analyzed at the MP2/DGDZVP//B3LYP/DGDZVP level of theory using the IEF-PCM method for taking into account the solvent acetonitrile (MeCN) effect. As the model substrates, styrene, trimethyl(vinyl)silane, dimethyl(divinyl)silane and diphenyl(divinyl)silane were chosen and mesylamide, triflamide, tosylamide and p-nosylamide were taken as the reagents. ButOI generated from ButOCl and NaI reacts with sulfonamides to give N-iodinated sulfonamides RSO2NHI and RSO2NI2 as active intermediates, the iodinating activity of the latter being notably higher. The analysis allowed to answer such challenging questions as different reactivity of nonfluorinated sulfonamides leading to aziridination and of triflamide resulting in the formation the main products of bis-triflamidation, or different regioselectivity of halogenation of styrene and trimethyl(vinyl)silane caused by a linear intermediate iodonium cation in the former case and a cyclic one in the latter.

Hazard identification and consumer safety characterization for trans-1-chloro-3,3,3-trifluoropropene (trans-1233zd).

Trans-1233zd was developed as a refrigerant and propellant in consumer products; its toxicity has been studied extensively. The scope of this assessment is to apply the confirmed NOAEC to conduct Benchmark Dose Modeling (BMD) and determine the Point of Departure (POD). In a previously published 13-week inhalation study, a NOAEC was identified at 4000 ppm. Due to uncertainty concerning the cardiac lesion, an external pathology peer review of heart tissues was undertaken using published best practices and consistent nomenclature and diagnostic criteria. The cardiac lesion observed at 4000 ppm was considered to be spontaneous based on lesion location and microscopic features. BMD was applied to derive the BMDL05 and BMDL10; the more conservative BMDL05 was used as the POD for risk assessment to calculate the Reference Exposure Levels (RELs). The 2-Box Air Dispersion Model was used to calculate the exposure to consumer products. Both the acute and chronic exposure concentrations calculated were compared to the acute and chronic RELs. The acute and chronic exposure to trans-1233zd in the assessed consumer products are below the RELs and deemed safe for their intended uses.

Rapid Syntheses of [11C]Arylvinyltrifluoromethanes through Treatment of (E)-Arylvinyl(phenyl)iodonium Tosylates with [11C]Trifluoromethylcopper(I).

We report a method for labeling arylvinyltrifluoromethanes with carbon-11 (t1/2 = 20.4 min) as representatives of a new radiolabeled chemotype that has potential for developing radiotracers for biomedical imaging with positron emission tomography. Treatment of (E)-arylvinyl(phenyl)iodonium tosylates (1a-1k) with [11C[CuCF3 gave the corresponding [11C]arylvinyltrifluoromethanes ([11C]2a-[11C]2k) in high radiochemical yields (90-97%) under rapid (2 min) and mild (60 °C) conditions.

18F-Trifluoromethanesulfinate Enables Direct C-H 18F-Trifluoromethylation of Native Aromatic Residues in Peptides.

18F labeling strategies for unmodified peptides with [18F]fluoride require 18F-labeled prosthetics for bioconjugation more often with cysteine thiols or lysine amines. Here we explore selective radical chemistry to target aromatic residues applying C-H 18F-trifluoromethylation. We report a one-step route to [18F]CF3SO2NH4 from [18F]fluoride and its application to direct [18F]CF3 incorporation at tryptophan or tyrosine residues using unmodified peptides as complex as recombinant human insulin. The fully automated radiosynthesis of octreotide[Trp(2-CF218F)] enables in vivo positron emission tomography imaging.

Negative-ion/positive-ion coincidence spectroscopy as a tool to identify anionic fragments: The case of core-excited CHF3.

We have studied the dissociation of the trifluoromethane molecule, CHF3 , into negative ionic fragments at the C 1s and F 1s edges. The measurements were performed by detecting coincidences between negative and positive ions. We observed five different negative ions: F- , H- , C- , CF- , and F2 - . Their production was confirmed by the analysis of triple coincidence events (negative-ion/positive-ion/positive-ion or NIPIPI coincidences) that were recorded with cleaner signals than those of the negative-ion/positive-ion coincidences. The intensities of the most intense NIPIPI coincidence channels were recorded as a function of photon energy across the C 1s and F 1s excitations and ionization thresholds. We also observed dissociation channels involving the formation of one negative ion and three positive ions. Our results demonstrate that negative-ion/positive-ion coincidence spectroscopy is a very sensitive method to observe anions, which at inner-shell edges are up to three orders of magnitude less probable dissociation products than cations.

A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a Z-Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole.

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, Z-chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F3C-substituted alkene can also be prepared with similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, generating mycothiazole in 14.5% overall yield.

A Gas Phase Route to [18F]fluoroform with Limited Molar Activity Dilution.

Positron emission tomography (PET) is an important imaging modality for biomedical research and drug development. PET requires biochemically selective radiotracers to realize full potential. Fluorine-18 (t1/2 = 109.8 min) is a major radionuclide for labeling such radiotracers but is only readily available in high activities from cyclotrons as [18F]fluoride ion. [18F]fluoroform has emerged for labeling tracers in trifluoromethyl groups. Prior methods of [18F]fluoroform synthesis used difluoro precursors in solution and led to high dilution with carrier and low molar activity (Am). We explored a new approach for the synthesis of [18F]fluoroform based on the radiosynthesis of [18F]fluoromethane from [18F]fluoride ion and then cobaltIII fluoride mediated gas phase fluorination. We estimate that carrier dilution in this process is limited to about 3-fold and find that moderate to high Am values can be achieved. We show that [18F]fluoroform so produced is highly versatile for rapidly and efficiently labeling various chemotypes that carry trifluoromethyl groups, thereby expanding prospects for developing new PET radiotracers.

Ultra-Short-Chain Perfluoroalkyl Acids Including Trifluoromethane Sulfonic Acid in Water Connected to Known and Suspected Point Sources in Sweden.

Data presenting the environmental occurrence of ultra-short-chain perfluoroalkyl acids (PFAAs) are scarce and little is known about the potential sources. In this study, ultra-short-chain PFAAs were analyzed in water connected to potential point sources using supercritical fluid chromatography coupled with tandem mass spectrometry. Samples (n = 34) were collected in connection with firefighting training sites, landfills, and a hazardous waste management facility. Ultra-short-chain PFAAs were detected in all samples at concentrations up to 84 000 ng/L (∑C1-C3), representing up to 69% of the concentration of 29 per- and polyfluoroalkyl substances (PFASs). Trifluoroacetic acid (TFA), perfluoropropanoic acid (PFPrA), trifluoromethane sulfonic acid (TFMS), perfluoroethane sulfonic acid (PFEtS), and perfluoropropane sulfonic acid (PFPrS) were detected at concentrations up to 14 000, 53 000, 940, 1700, and 15 000 ng/L, respectively. Principal component analysis suggests that TFA is associated with landfills. PFPrS was associated with samples collected close to the source at all types of sites included in this study. These findings reveal the presence of high concentrations of ultra-short-chain PFAAs released into the environment from various sources and emphasize the large fraction of ultra-short-chain PFAAs to the total concentration of PFASs in water.

Feasibility of trifluoromethyl TROSY NMR at high magnetic fields.

Insights into the structure and dynamics of large biological systems has been greatly improved by two concurrent NMR approaches: the application of transverse relaxation-optimized spectroscopy (TROSY) techniques in multi-dimensional NMR, especially the methyl-TROSY, and the resurgence of 19F NMR using trifluoromethyl (CF3) probes. Herein we investigate the feasibility of combining these approaches into a trifluoromethyl-TROSY experiment. Using a CF3-labelled parvalbumin, we have evaluated the natural abundance 13C-19F correlation spectra and find no indication of a CF3 TROSY at high magnetic fields.

Catalytic Performance of Nitrogen-Doped Activated Carbon Supported Pd Catalyst for Hydrodechlorination of 2,4-Dichlorophenol or Chloropentafluoroethane.

Nitrogen-doped activated carbon (N-AC) obtained through the thermal treatment of a mixture of HNO3-pretreated activated carbon (AC) and urea under N2 atmosphere at 600 °C was used as the carrier of Pd catalyst for both liquid-phase hydrodechlorination of 2,4-dichlorophenol (2,4-DCP) and gas-phase hydrodechlorination of chloropentafluoroethane (R-115). The effects of nitrogen doping on the dispersion and stability of Pd, atomic ratio of Pd/Pd2+ on the surface of the catalyzer, the catalyst's hydrodechlorination activity, as well as the stability of N species in two different reaction systems were investigated. Our results suggest that, despite no improvement in the dispersion of Pd, nitrogen doping may significantly raise the atomic ratio of Pd/Pd2+ on the catalyst surface, with a value of 1.2 on Pd/AC but 2.2 on Pd/N-AC. Three types of N species, namely graphitic, pyridinic, and pyrrolic nitrogen, were observed on the surface of Pd/N-AC, and graphitic nitrogen was stable in both liquid-phase hydrodechlorination of 2,4-DCP and gas-phase hydrodechlorination of R-115, with pyridinic and pyrrolic nitrogen being unstable during gas-phase hydrodechlorination of R-115. As a result, the average size of Pd nanocrystals on Pd/N-AC was almost kept unchanged after liquid-phase hydrodechlorination of 2,4-DCP, whereas crystal growth of Pd was clearly observed on Pd/N-AC after gas-phase hydrodechlorination of R-115. The activity test revealed that Pd/N-AC exhibited a much better performance than Pd/AC in liquid-phase hydrodechlorination of 2,4-DCP, probably due to the enhanced stability of Pd exposed to the environment resulting from nitrogen doping as suggested by the higher atomic ratio of Pd/Pd2+ on the catalyst surface. In the gas-phase hydrodechlorination of R-115, however, a more rapid deactivation phenomenon occurred on Pd/N-AC than on Pd/AC despite a higher activity initially observed on Pd/N-AC, hinting that the stability of pyridinic and pyrrolic nitrogen plays an important role in the determination of catalytic performance of Pd/N-AC.

The development of environmentally acceptable fluorocarbons.

Chlorofluorocarbons (CFCs) were introduced in the 1930s as the safe replacements for the toxic and flammable refrigerants being used at that time. Subsequently, hydrochlorofluorocarbons (HCFCs) were also developed. In addition to refrigerant applications, they were used as foam blowing agents, as solvents and as propellants for many aerosols. In the 1970s and 1980s, concern developed about their environmental impact, specifically on stratospheric ozone depletion. Industry began to consider acceptable replacements. In 1987, many of the governments of the world came together and drafted the Montreal Protocol, calling upon Industry to initially phase out production of the CFCs and later HCFCs. Within 4 months of the signing of the Montreal Protocol, the 15 global major producers joined together to form the Alternative Fluorocarbons Environmental Acceptability Study (AFEAS), which sponsored research into environmental effects and the Program for Alternative Fluorocarbons toxicity Testing, PAFT), which examined the toxicology of potential replacements for the CFCs and HCFCs. Nine replacements were identified by companies and, through this international cooperation; toxicology programs were designed, conducted, and evaluated without duplication of effort and testing; consequently these new products were introduced within less than 10 years. Indeed the Montreal Protocol has been recognized as the most appropriate international treaty to phase-down HFCs. In 2016 the Kigali Amendment to the Montreal Protocol set out a phase-down schedule for the consumption and production of HFCs. In order to reduce the consumption and emissions of high GWP HFCs. Recently lower GWP HFCs and very low GWP HFOs (hydrofluoroolefins and HCFOs (hydrochlorofluoroolefins) have been introduced into a range of applications. Summaries of the toxicology profiles of some of the original CFCs and HCFCs, the replacements and the new post-PAFT replacements are described. The chemicals in this review include CFC-11, CFC-12, CFC-113, CFC-114, HCFC 22, HCFC-123, HCFC-124, HCFC-141b, HCFC-142b, HCF-32, HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-245ea, HFC-245fa, HFO-1234yf, HFO-1234ze, and HCFO-1233zd.

Redox-Active Reagents for Photocatalytic Generation of the OCF3 Radical and (Hetero)Aryl C-H Trifluoromethoxylation.

The trifluoromethoxy (OCF3 ) radical is of great importance in organic chemistry. Yet, the catalytic and selective generation of this radical at room temperature and pressure remains a longstanding challenge. Herein, the design and development of a redox-active cationic reagent (1) that enables the formation of the OCF3 radical in a controllable, selective, and catalytic fashion under visible-light photocatalytic conditions is reported. More importantly, the reagent allows catalytic, intermolecular C-H trifluoromethoxylation of a broad array of (hetero)arenes and biorelevant compounds. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1 resulting in exclusive liberation of the OCF3 radical. Addition of this radical to (hetero)arenes gives trifluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of trifluoromethoxylation.

Metallaphotoredox Difluoromethylation of Aryl Bromides.

Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl-radical-mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late-stage functionalization of several drug analogues.

Unexpected, Latent Radical Reaction of Methane Propagated by Trifluoromethyl Radicals.

Thorough mechanistic studies and DFT calculations revealed a background radical pathway latent in metal-catalyzed oxidation reactions of methane at low temperatures. Use of hydrogen peroxide with TFAA generated a trifluoromethyl radical (•CF3), which in turn reacted with methane gas to selectively yield acetic acid. It was found that the methyl carbon of the product was derived from methane, while the carbonyl carbon was derived from TFAA. Computational studies also support these findings, revealing the reaction cycle to be energetically favorable.