Iron(II)-Catalyzed 1,2-Diamination of Styrenes Installing a Terminal NH2 Group Alongside Unprotected Amines.

1,2-Diamination of alkenes represents an attractive way to generate differentiated vicinal diamines, which are prevalent motifs in biologically active compounds and catalysts. However, existing methods are usually limited in scope and produce diamines where one or both nitrogens are protected, adding synthetic steps for deprotection and further N-functionalization to reach a desired target. Furthermore, the range of amino groups that can be introduced at the internal position is fairly limited. Here we describe a 1,2-diamination of styrenes that directly installs a free amino group at the terminal position and a wide variety of unprotected nitrogen nucleophiles (primary or secondary alkyl or aromatic amines, sulfoximines, N-heterocycles, and ammonia surrogate) at the internal position. Two complementary sets of conditions encompass electronically activated and deactivated styrenes with diverse substitution patterns and functional groups. Moreover, this strategy can be extended to the 1,2-aminothiolation of styrenes.

Cooperative Friedel-Crafts Alkylation of Electron-Deficient Arenes via Catalyst Activation with Hexafluoroisopropanol.

A Friedel-Crafts alkylation of electron-deficient arenes with aldehydes through ''catalyst activation'' is presented. Through hydrogen bonding interactions, the solvent 1,1,1,3,3,3, -hexafluoroisopropanol (HFIP) interacted with the added Brønsted acid catalyst pTSA•H2 O, increasing its acidity. This activated catalyst enabled the Friedel-Crafts alkylation of electron-neutral as well as electron-deficient arenes. Strongly electron withdrawing arenes including arenes with multiple halogen atoms, NO2 , CHO, CO2 R, and CN, groups acted as efficient nucleophiles in this reaction. DFT studies reveal multiple roles of solvent HFIP viz; increasing the Brønsted acidity of the catalyst pTSA•H2 O, and stabilization of the transition states through a concerted pathway enabling the challenging reaction.

Synthesis of Unprotected ß-Arylethylamines by Iron(II)-Catalyzed 1,2-Aminoarylation of Alkenes in Hexafluoroisopropanol.

ß-Arylethylamines are prevalent structural motifs in molecules exhibiting biological activity. Here we report a sequential one-pot protocol for the 1,2-aminoarylation of alkenes with hydroxylammonium triflate salts and (hetero)arenes. Unlike existing methods, this reaction provides a direct entry to unprotected ß-arylethylamines with remarkable functional group tolerance, allowing key drug-oriented functional groups to be installed in a two-step process. The use of hexafluoroisopropanol as a solvent in combination with an iron(II) catalyst proved essential to reaching high-value nitrogen-containing molecules.

Experimental and Theoretical Investigation of an Azaoxyallyl Cation-Templated Intramolecular Aryl Amination Leading to Oxindole Derivatives.

Herein, development and detailed investigation of a SN '-type intramolecular aromatic substitution reaction involving α-arylazaoxyallyl cation intermediate, is disclosed. The study showcased that while α-aryl-α-chlorohydroxamate could be activated by a combination of base and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) into the corresponding azaoxyallyl cations, it could further emerge into a π-extended species involving the adjacent α-aryl moiety, and this transition is contingent on electronic effects of the aromatic ring as well as on α-substituents. An effective activation of the α-aromatic ring could pave the path for intramolecular Ar(Csp2 )-N bond formation towards oxindoles. Control experiments and DFT calculations suggested that a non-pericyclic nucleophilic amination pathway is most likely operative and precluded the possibility of concerted or electrophilic amination mechanism. HFIP as the reaction solvent plays pivotal roles in the transformation.

Hydrogen Bonding and Vaporization Thermodynamics in Hexafluoroisopropanol-Acetone and -Methanol Mixtures. A Joined Cluster Analysis and Molecular Dynamic Study.

Binary mixtures of hexafluoroisopropanol with either methanol or acetone are analyzed via classical molecular dynamics simulations and quantum cluster equilibrium calculations. In particular, their populations and thermodynamic properties are investigated with the binary quantum cluster equilibrium method, using our in-house code Peacemaker 2.8, upgraded with temperature-dependent parameters. A novel approach, where the final density from classical molecular dynamics, has been used to generate the necessary reference isobars. The hydrogen bond network in both type of mixtures at molar fraction of hexafluoroisopropanol of 0.2, 0.5, and 0.8 respectively is investigated via the molecular dynamics trajectories and the cluster results. In particular, the populations show that mixed clusters are preferred in both systems even at 0.2 molar fractions of hexafluoroisopropanol. Enthalpies and entropies of vaporization are calculated for the neat and mixed systems and found to be in good agreement with experimental values.

Ultra-Short-Chain PFASs in the Sources of German Drinking Water: Prevalent, Overlooked, Difficult to Remove, and Unregulated.

Per- and polyfluoroalkyl substances (PFASs) have been a focal point of environmental chemistry and chemical regulation in recent years, culminating in a shift from individual PFAS regulation toward a PFAS group regulatory approach in Europe. PFASs are a highly diverse group of substances, and knowledge about this group is still scarce beyond the well-studied, legacy long-chain, and short-chain perfluorocarboxylates (PFCAs) and perfluorosulfonates (PFSAs). Herein, quantitative and semiquantitative data for 43 legacy short-chain and ultra-short-chain PFASs (≤2 perfluorocarbon atoms for PFCAs, ≤3 for PFSAs and other PFASs) in 46 water samples collected from 13 different sources of German drinking water are presented. The PFASs considered include novel compounds like hexafluoroisopropanol, bis(trifluoromethylsulfonyl)imide, and tris(pentafluoroethyl)trifluorophosphate. The ultra-short-chain PFASs trifluoroacetate, perfluoropropanoate, and trifluoromethanesulfonate were ubiquitous and present at the highest concentrations (98% of sum target PFAS concentrations). "PFAS total" parameters like the adsorbable organic fluorine (AOF) and total oxidizable precursor (TOP) assay were found to provide only an incomplete picture of PFAS contamination in these water samples by not capturing these highly prevalent ultra-short-chain PFASs. These ultra-short-chain PFASs represent a major challenge for drinking water production and show that regulation in the form of preventive measures is required to manage them.

Highly Z-Selective Horner-Wadsworth-Emmons Olefination Using Modified Still-Gennari-Type Reagents.

In this report, new, easily accessible reagents for highly Z-selective HWE reactions are presented. Alkyl di-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetates, structurally similar to Still-Gennari type reagents, were tested in HWE reactions with a series of various aldehydes. Very good Z-selectivity (up to a 98:2 Z:E ratio) was achieved in most cases along with high yields. Application of the new reagents may be a valuable, practical alternative to the well-established Still-Gennari or Ando Z-selective carbonyl group olefination protocols.

Alcohols as Alkylating Agents in the Cation-Induced Formation of Nitrogen Heterocycles.

A Ti(Oi-Pr)4 promoted 5- or 6-endo-trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di- & tri-substituted pyrrolidines and piperidines while forming a new C-C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C-C and a C-N bond in a single step. Notably, either 2,3-trans- or 2,3-cis-substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.

Direct Dehydrogenative Access to Unsymmetrical Phenones.

The first non-directed dehydrogenative phenone coupling method of methylarenes with aromatic C-H bonds, displaying a large substrate scope, is herein reported. This reaction represents a far more direct atom- and step-efficient alternative to the classical Friedel-Crafts or Suzuki-Miyaura derived acylation reactions. The method can be carried out on a gram scale and was successfully applied to the synthesis of several Ketoprofen drug analogues.

Promoting the Furan Ring-Opening Reaction to Access New Donor-Acceptor Stenhouse Adducts with Hexafluoroisopropanol.

Donor-acceptor Stenhouse adducts (DASAs) are visible-light-responsive photoswitches with a variety of emerging applications in photoresponsive materials. Their two-step modular synthesis, centered on the nucleophilic ring opening of an activated furan, makes DASAs readily accessible. However, the use of less reactive donors or acceptors renders the process slow and low yielding, which has limited their development. We demonstrate here that 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) promotes the ring-opening reaction and stabilizes the open isomer, allowing greatly reduced reaction times and increased yields for known derivatives. In addition, it provides access to previously unattainable DASA-based photoswitches and DASA-polymer conjugates. The role of HFIP and the photochromic properties of a set of new DASAs is probed using a combination of 1 H NMR and UV/Vis spectroscopy. The use of sterically hindered, electron-poor amines enabled the dark equilibrium to be decoupled from closed-isomer half-lives for the first time.

Brønsted Acid and H-Bond Activation in Boronic Acid Catalysis.

Boronic acid catalysis has emerged as a mild method for promoting a wide variety of reactions. It has been proposed that the mode of catalysis involves Lewis acid or covalent activation of hydroxyl groups by boron, but limited mechanistic evidence exists. In this work, representative boronic acid catalyzed reactions of alcohols and oximes have been reinvestigated. A series of control experiments with boronic and Brønsted acids were interpreted along with correlations between their reactivity and their acidity measured by the Gutmann-Beckett method. Overall, it was concluded that the major modes of catalysis involve either dual H-bond catalysis or Brønsted acid catalysis. Strong Brønsted acids were shown to be generated in situ from covalent assembly of the boronic acids with hexafluoroisopropanol, explaining why the solvent had such a major impact on the reactivity. This new insight should guide the future development of boronic acid catalysis, where the diverse and solvent-specific nature of catalytic modes has been overlooked.

The Affinity of Some Lewis Bases for Hexafluoroisopropanol as a Reference Lewis Acid: An ITC/DFT Study.

To figure out the possible role of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as well as to provide reference thermochemical data in solution, the formation of Lewis acid-base complexes between HFIP (Lewis acid) and a series of 8 different Lewis bases (3 sulfoxides, 3 Nsp2 pyridine derivatives, 1 aromatic amine, 1 cyclic aliphatic ether) was examined by isothermal titration calorimetry (ITC) experiments and static density functional theory augmented with Dispersion (DFT-D) calculations. Measured ITC association enthalpy values (ΔHa ) lie between -9.3 and -14 kcal mol-1 . Computations including a PCM implicit solvation model produced similar exothermicity of association of all studied systems compared to the ITC data with ΔHa values ranging from -8.5 to -12.7 kcal mol-1 . An additional set of calculations combining implicit and explicit solvation by chlorobenzene of the reactants, pointed out the relatively low interference of the solvent with the HFIP-base complexation: its main effect is to slightly enhance the Gibbs energy of the HFIP-Lewis base association. It is speculated that the interactions of bulk HFIP with Lewis bases therefore may significantly intervene in catalytic processes not only via the dynamic microstructuring of the medium but also more explicitly by affecting bonds' polarization at the Lewis bases.

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis.

Fluorinated alcohols have been widely used in the synthetic organic chemistry over the past decades. The unique properties such as the strong hydrogen-bonding donor ability and low nucleophilicity allow them to promote organic reactions in the absence of any catalyst. These approaches have distinct advantages in terms of operational simplicity, practicability and environmental friendliness. Reactions promoted by fluorinated alcohols, including nucleophilic substitution reactions, annulation reactions, electrophilic reactions, dearomatization reactions, functionalization of multiple bond, epoxidation reactions and miscellaneous reactions have been summarized in this account.

Synthesis of Bridged Tetrahydrobenzo[b]azepines and Derivatives through an Aza-Piancatelli Cyclization/Michael Addition Sequence.

Herein, we report the preparation of bridged tetrahydrobenzo[b]azepines, which was accomplished through an aza-Piancatelli cyclization/Michael addition sequence in a one-pot fashion from readily available precursors. It is noteworthy that a general method to access these scaffolds was hitherto unprecedented. Additionally, the multifaceted aspects of this process have been exemplified through its application to the synthesis of 2-azabicyclo[3.2.1]octanes and bridged tetrahydrobenzo[b]oxepines, along with post-derivatizations.

HFIP-Functionalized Co3 O4 Micro-Nano-Octahedra/rGO as a Double-Layer Sensing Material for Chemical Warfare Agents.

Semiconductor metal oxides (SMO)-based gas-sensing materials suffer from insufficient detection of a specific target gas. Reliable selectivity, high sensitivity, and rapid response-recovery times under various working conditions are the main requirements for optimal gas sensors. Chemical warfare agents (CWA) such as sarin are fatal inhibitors of acetylcholinesterase in the nerve system. So, sensing materials with high sensitivity and selectivity toward CWA are urgently needed. Herein, micro-nano octahedral Co3 O4 functionalized with hexafluoroisopropanol (HFIP) were deposited on a layer of reduced graphene oxide (rGO) as a double-layer sensing materials. The Co3 O4 micro-nano octahedra were synthesized by direct growth from electrospun fiber templates calcined in ambient air. The double-layer rGO/Co3 O4 -HFIP sensing materials presented high selectivity toward DMMP (sarin agent simulant, dimethyl methyl phosphonate) versus rGO/Co3 O4 and Co3 O4 sensors after the exposure to various gases owing to hydrogen bonding between the DMMP molecules and Co3 O4 -HFIP. The rGO/Co3 O4 -HFIP sensors showed high stability with a response signal around 11.8 toward 0.5 ppm DMMP at 125 °C, and more than 75 % of the initial response was maintained under a saturated humid environment (85 % relative humidity). These results prove that these double-layer inorganic-organic composite sensing materials are excellent candidates to serve as optimal gas-sensing materials.

Chemospecific Cyclizations of α-Carbonyl Sulfoxonium Ylides on Aryls and Heteroaryls.

The functionalization of aryl and heteroaryls using α-carbonyl sulfoxonium ylides without the help of a directing group has remained so far a neglected area, despite the advantageous safety profile of sulfoxonium ylides. Described herein are the cyclizations of α-carbonyl sulfoxonium ylides onto benzenes, benzofurans and N-p-toluenesulfonyl indoles in the presence of a base in HFIP, whereas pyrroles and N-methyl indoles undergo cyclization in the presence of an iridium catalyst. Significantly, these two sets of conditions are chemospecific for each groups of substrates.

The Un(f)told Story of General Anesthesia.

Inhalational anesthetics are routinely employed in clinical practice to accomplish general anesthesia. Concerns have recently emerged regarding the deleterious impact of these volatile agents on cognitive performance, immune functions, and tumor recurrence and metastasis. These agents have been shown to modify the gene-expression pattern as well as cell signaling in tumor cells, but the underlying molecular mechanisms remain a matter of conjecture. Regulatory/signaling proteins either of cytosolic or membrane origin abundantly contain intrinsically disordered sequences, the conformational pliability of which is pivotal in their biological functions. It is well known that chloroform (an anesthetic itself), trifluoroethanol, hexafluoroisopropanol, and related haloalcohols markedly affect the structure of disordered proteins and protein regions by inducing folding, misfolding, or even aggregation. Taking into consideration the physicochemical similarities and protein interaction modes of these volatile solvents and inhaled anesthetics, it is postulated that administration of these drugs can also modify the secondary structure of disordered protein segments. Accordingly, pharmacological effects of anesthetics may, at least in part, be mediated by conformational perturbations of intrinsic disorder-based regulatory protein networks of cells.

Calcium(II)-Catalyzed Intermolecular Hydroarylation of Deactivated Styrenes in Hexafluoroisopropanol.

A challenging catalytic hydroarylation of highly electron deficient styrenes has been developed on the basis of efficient cooperation between a calcium(II) triflimide salt and hexafluoroisopropanol (HFIP). This method affords a large variety of diaryl alkanes, notably diaryl ethanes, in good to excellent yields, and is simple to implement and compatible with various functional groups. Furthermore, DFT calculations and deuterium labeling experiments were conducted to elucidate the function of this promoter system.

Hexafluoroisopropanol-induced catanionic-surfactants-based coacervate extraction for analysis of lysozyme.

A coacervate extraction method, based on hexafluoroisopropanol (HFIP)-induced catanionic surfactants and coupled with a back-extraction procedure, was developed for separation and purification of proteins, using sodium dodecyl sulfate (SDS) and dodecyltrimethyl ammonium bromide (DTAB) as representative catanionic surfactants and lysozyme as a model protein. After the coacervate extraction and back extraction, the obtained lysozyme solutions were examined in terms of quantitative analysis by capillary electrophoresis, bacteriolytic activity, and circular dichroism (CD). The effects of several parameters including back-extraction solvent, HFIP content, total surfactant concentration, and SDS/DTAB molar ratio were investigated in detail on the extraction efficiency and activity of lysozyme. Under the optimized extraction conditions (66 mM KH2PO4 buffer with pH 6.2 as back-extraction solvent, SDS/DTAB molar ratio = 1:1 mol/mol, total surfactant concentration = 30 mM, HIFP concentration = 8 % v/v), the extraction recovery was 89.8 % (±4.7, n = 3), limit of detection was 2.2 (±0.3, n = 3) µg mL-1, and meanwhile nearly 65 % of native lysozyme activity was retained. In addition, the activity and CD assays showed that SDS/DTAB molar ratio had a significant influence on the activity and structure of lysozyme after extraction. The DTAB-rich extraction systems, in which the DTAB mole fraction was equal to or larger than 70 %, could keep the activity and structure of lysozyme almost in the native state. Graphical Abstract Procedure of HFIP-induced SDS/DTAB coacervate extraction and back extraction of lysozyme.

Signal Enhancement in the HPLC-ESI-MS/MS analysis of spironolactone and its metabolites using HFIP and NH4F as eluent additives.

This paper describes an LC-MS/MS method to determine the concentration of spironolactone and its metabolites 7-alpha-methylthiospironolactone and canrenone in blood plasma samples. The resulting assay is simple (using protein precipitation for sample preparation) and sensitive (the lower limit of quantification is close to 0.5 ng/ml) while requiring only 50 µl of plasma, making it especially suitable for analyzing samples obtained from pediatric and neonatal patients where sample sizes are limited. The sensitivity is achieved by using ammonium fluoride as an eluent additive, which in our case amplifies the signal from our analytes in the plasma solution on average about 70 times. The method is fully validated according to the European Medicines Agency's guideline and used for the measurement of pediatric patients' samples in clinical trials for evaluating oral spironolactone's and its metabolites' pharmacokinetics in children up to 2 years of age.