Photomediated Hexafluoroisopropoxylation of Unactivated Aryl Halides.

The use of fluoroalkoxy groups, such as trifluoromethoxy and 2,2,2-trifluoroethoxy groups, in pharmaceutical and agrochemical development has increased dramatically in recent years. However, hexafluoroisopropoxy groups have remained significantly underrepresented, presumably due to limited synthetic methods for accessing this substituent in good yields. Herein, we report a mild, photochemical nucleophilic aromatic substitution (SNAr) approach for the synthesis of hexafluoroisopropyl aryl ethers from unactivated and abundant aryl halides. Notably, aryl chloride and bromide functionality are efficiently engaged by this methodology in addition to the traditional aryl fluoride nucleofuge. This method provided access to a diverse array of hexafluoroisopropyl aryl ethers, including multiple examples of late-stage functionalization of active pharmaceutical ingredients. A simple flow system was adapted for 10x scale-up, maintaining good yield for the reaction. Initial mechanistic studies indicate single electron oxidation of the arene as a key step in product formation.

Metal-Free Selective Synthesis of α,ß-Unsaturated Aldehydes from Alkenes and Formaldehyde Catalyzed by Dimethylamine.

α,ß-Unsaturated aldehydes are important building blocks for the synthesis of a wide range of chemicals, including polymers. The synthesis of these molecules from cheap feedstocks such as alkenes remains a scientific challenge, mainly due to the low reactivity of alkenes. Here we report a selective and metal-free access to α,ß-unsaturated aldehydes from alkenes with formaldehyde. This reaction is catalyzed by dimethylamine and affords α,ß-unsaturated aldehydes in yields of up to 80 %. By combining Density Functional Theory (DFT) calculations and experiments, we elucidate the reaction mechanism which is based on a cascade of hydride transfer, hydrolysis and aldolization reactions. The reaction can be performed under very mild conditions (30-50 °C), in a theoretically 100 % carbon-economical fashion, with water as the only by-product. The reaction was successfully applied to non-activated linear 1-alkenes, thus opening an access to industrially relevant α,ß-unsaturated aldehydes from cheap and widely abundant chemicals at large scale.

Mechanochemical Regioselective [3+3] Annulation of 6-Amino Uracil with Propargyl Alcohols Catalyzed by a Brønsted Acid/Hexafluoroisopropanol.

A mechanochemistry approach is developed for regioselective synthesis of functionalized dihydropyrido[2,3-d]pyrimidines by milling propargylic alcohols and 6-aminouracils with HFIP/p-TsOH. In the case of tert-propargyl alcohols, this [3+3] cascade annulation proceeded through allenylation of uracil followed by a 6-endo trig cyclization. With sec-propargyl alcohols, the reaction furnished the propargylation of uracil. This atom economy ball milling reaction allows access to a broad range of dihydropyrido[2,3-d]pyrimidine derivatives in excellent yields. We demonstrated the gram scale synthesis of 3 g and post-synthetic modifications to effect the cyclization of 5 to 6.

Upgrading of the general AMBER force field 2 for fluorinated alcohol biosolvents: A validation for water solutions and melittin solvation.

The standard GAFF2 force field parameterization has been refined for the fluorinated alcohols 2,2,2-trifluoroethanol (TFE), 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), and 1,1,1,3,3,3-hexafluoropropan-2-one (HFA), which are commonly used to study proteins and peptides in biomimetic media. The structural and dynamic properties of both proteins and peptides are significantly influenced by the biomimetic environment created by the presence of these cosolvents in aqueous solutions. Quantum mechanical calculations on stable conformers were used to parameterize the atomic charges. Different systems, such as pure liquids, aqueous solutions, and systems formed by melittin protein and cosolvent/water solutions, have been used to validate the new models. The calculated macroscopic and structural properties are in agreement with experimental findings, supporting the validity of the newly proposed models.

Alcohols as Efficient Intermolecular Initiators for a Highly Stereoselective Polyene Cyclisation Cascade.

The use of benzylic and allylic alcohols in HFIP solvent together with Ti(Oi Pr)4 has been shown to trigger a highly stereoselective polyene cyclisation cascade. Three new carbon-carbon bonds are made during the process and complete stereocontrol of up to five new stereogenic centers is observed. The reaction is efficient, has high functional group tolerance and is atom-economic generating water as a stoichiometric by-product. A new polyene substrate-class is employed, and subsequent mechanistic studies indicate a stereoconvergent mechanism. The products of this reaction can be used to synthesize steroid-analogues in a single step.

Ab Initio Metadynamics Simulations of Hexafluoroisopropanol Solvent Effects: Synergistic Role of Solvent H-Bonding Networks and Solvent-Solute C-H/π Interactions.

The solvent effects in Friedel-Crafts cycloalkylation of epoxides and Cope rearrangement of aldimines were investigated by using ab initio molecular dynamics simulations. Explicit molecular treatments were applied for both reactants and solvents. The reaction mechanisms were elucidated via free energy calculations based on metadynamics simulations. The results reveal that both reactions proceed in a concerted fashion. Key solvent-substrate interactions are identified from the structures of transition states with explicit solvent molecules. The remarkable promotion effect of hexafluoroisopropanol solvent is ascribed to the synergistic effect of H-bonding networks and C-H/π interactions with substrates.

1,1,1,3,3,3-Hexafluoro-2-Propanol-Promoted Friedel-Crafts Reaction: Metal-Free Synthesis of C3-Difluoromethyl Carbinol-Containing Imidazo[1,2-a]pyridines at Room Temperature.

A facile and efficient method has been developed for the synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature via the HFIP-promoted Friedel-Crafts reaction of difluoroacetaldehyde ethyl hemiacetal and imidazo[1,2-a]pyridines. This strategy could be applied to the direct C(sp2)-H hydroxydifluoromethylation of imidazo[1,2-a]pyridines and afford a series of novel difluoromethylated carbinols in good to satisfactory yields with 29 examples. Furthermore, gram-scale and synthetic transformation experiments have also been achieved, demonstrating its potential applicable value in organic synthesis. This green protocol has several advantages, including being transition metal- and oxidant-free, being carried out at room temperature, having high efficiency, and having a wide substrate scope.

Indole Editing Enabled by HFIP-Mediated Ring-Switch Reactions of 3-Amino-2-Hydroxyindolines.

This work reports the novel reactivity of hemiaminal as a precursor for indole editing at the multi-site. The HFIP-promoted indole editing of indoline hemiaminals affords 2-arylindoles through a ring-switch sequence. The key to success of this transformation is to use a cyclic hemiaminal as an α-amino aldehyde surrogate under transient tautomeric control. This transformation features mild reaction conditions and good yields with broad functional group tolerance. The utility of this transformation is presented through the one-pot protocol and the synthesis of isocryptolepine.

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.

Structure of AQEE-30 of VGF Neuropeptide in Membrane-Mimicking Environments.

AQEE-30 is one of the VGF peptides, which are derived from the VGF polypeptide precursor, and related to various physiological phenomena including neuroprotective effects in Huntington's disease and amyotrophic lateral sclerosis (ALS). Although various functions of AQEE-30 have been reported so far, the structure of this peptide has not been reported yet. In this study, the structure of human AQEE-30 was investigated in hexafluoroisopropanol (HFIP) and dodecyl phosphocholine (DPC) micelle solutions, using circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. CD results showed that AQEE-30 had a partial helical structure in aqueous buffer, and the helical structure was stabilized in the HFIP and DPC micelle solutions. The 3D structures determined by NMR spectroscopy showed that AQEE-30 adopted mainly α-helical structure in both the HFIP and DPC micelle solutions. The surface of AQEE-30 showed that it was predominantly negatively charged. The residues from 601 to 611 in both the HFIP and DPC micelle solutions showed amphiphilicity with four negatively charged residues, glutamate. The C-terminal consecutive arginine residues formed a partial positively charged surface. These results suggest an α-helical active structure of AQEE-30 in the cell-membrane environment.

Hydrogen Bonding Networks Enable Brønsted Acid-Catalyzed Carbonyl-Olefin Metathesis.

Synthetic chemists have learned to mimic nature in using hydrogen bonds and other weak interactions to dictate the spatial arrangement of reaction substrates and to stabilize transition states to enable highly efficient and selective reactions. The activation of a catalyst molecule itself by hydrogen-bonding networks, in order to enhance its catalytic activity to achieve a desired reaction outcome, is less explored in organic synthesis, despite being a commonly found phenomenon in nature. Herein, we show our investigation into this underexplored area by studying the promotion of carbonyl-olefin metathesis reactions by hydrogen-bonding-assisted Brønsted acid catalysis, using hexafluoroisopropanol (HFIP) solvent in combination with para-toluenesulfonic acid (pTSA). Our experimental and computational mechanistic studies reveal not only an interesting role of HFIP solvent in assisting pTSA Brønsted acid catalyst, but also insightful knowledge about the current limitations of the carbonyl-olefin metathesis reaction.

HFIP-Assisted Single C-F Bond Activation of Trifluoromethyl Ketones using Visible-Light Photoredox Catalysis.

A visible light photoredox catalytic method for the selective cleavage of single strong C-F bond in trifluoromethyl ketones is reported. Single electron reduction of trifluoromethyl ketones generates difluoromethyl radicals which can be engaged in intermolecular C-C bond formation with N-methyl-N-arylmethacrylamides to furnish fluorine-containing oxindole derivatives in good yields. The reaction shows excellent chemoselectivity with good functional group tolerance under mild conditions. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) as a solvent plays a critical role for the selective single C-F bond cleavage. High-level DFT calculations are depicted to shed light on the mechanism.

Dual XH-π Interaction of Hexafluoroisopropanol with Arenes.

The dual XH (OH and CH) hydrogen-bond-donating property of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and the strong dual XH-π interaction with arenes were firstly disclosed by theoretical studies. Here, the high accuracy post-Hartree-Fock methods, CCSD(T)/CBS, reveal the interaction energy of HFIP/benzene complex (-7.22 kcal/mol) and the contribution of the electronic correlation energy in the total interaction energy. Strong orbital interaction between HFIP and benzene was found by using the DFT method in this work to disclose the dual XH-π intermolecular orbital interaction of HFIP with benzene-forming bonding and antibonding orbitals resulting from the orbital symmetry of HFIP. The density of states and charge decomposition analyses were used to investigate the orbital interactions. Isopropanol (IP), an analogue of HFIP, and chloroform (CHCl3) were studied to compare them with the classical OH-π, and non-classical CH-π interactions. In addition, the influence of the aggregating effect of HFIP, and the numbers of substituted methyl groups in benzene rings were also studied. The interaction energies of HFIP with the selected 24 common organic compounds were calculated to understand the role of HFIP as solvent or additive in organic transformation in a more detailed manner. A single-crystal X-ray diffraction study of hexafluoroisopropyl benzoate further disclosed and confirmed that the CH of HFIP shows the non-classical hydrogen-bond-donating behavior.

Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones.

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

HFIP-Promoted de Novo Synthesis of Biologically Relevant Nonnatural α-Arylated Amino Esters and Dipeptide Mimetics.

Amino acids are fundamental building blocks, which have been extensively used in drug design and organic synthesis. However, nonnatural amino acids are relatively less studied. In this work, the authors report the first HFIP-promoted de novo synthesis of nonnatural α-arylated amino esters and dipeptide mimetics (27 examples, up to 99 % yield) from readily available amines, ethyl glyoxylate and electron-rich arenes under mild conditions, in which one C-C bond, one C-N bond and one chiral center were established simultaneously. The reaction was also performed on a gram scale, giving compound 4 a in 96 % yield. In addition, this protocol was successfully applied to the late-stage elaboration of drug molecules, such as tranylcypromine (TCP or PCPA) and troxipide. Interestingly, compound 4 h inactivated histone lysine specific demethylase 1 (LSD1) potently with an IC50 value of 0.296 µm. To the best of our knowledge, compound 4 h is the first LSD1 inhibitor derived from nonnatural α-arylated amino esters, and therefore could be used as a hit compound for the development of new LSD1 inhibitors. The synthesized nonnatural α-arylated amino esters and dipeptide mimetics as unique building blocks may have potential synthetic utilities.

Conversion of Fructose to HMF in a Continuous Fixed Bed Reactor with Outstanding Selectivity.

5-Hydroxymethylfurfural (HMF) is a very promising component for bio-based plastics. Efficient synthesis of HMF from biomass is still challenging because of fast degradation of HMF to by-products under formation conditions. Therefore, different studies, conducted mainly in monophasic and biphasic batch systems with and without water addition have been published and are still under investigation. However, to produce HMF at a large scale, a continuous process is preferable. Until now, only a few studies have been published in this context. In this work, it is shown that fluorous alcohol hexafluoroisopropanol (HFIP) can act as superior reaction solvent for HMF synthesis from fructose in a fixed bed reactor. Very high yields of 76% HMF can be achieved in this system under optimized conditions, whilst the catalyst is very stable over several days. Such high yields are only described elsewhere with high boiling reaction solvents like dimethylsulfoxide (DMSO), whereas HFIP with a boiling point of 58 °C is very easy to separate from HMF.

Catalytic Dehydration of Fructose to 5-Hydroxymethylfurfural (HMF) in Low-Boiling Solvent Hexafluoroisopropanol (HFIP).

A mixture of hexafluoroisopropanol (HFIP) and water was used as a new and unknown monophasic reaction solvent for fructose dehydration in order to produce HMF. HFIP is a low-boiling fluorous alcohol (b.p. 58 °C). Hence, HFIP can be recovered cost efficiently by distillation. Different ion-exchange resins were screened for the HFIP/water system in batch experiments. The best results were obtained for acidic macroporous ion-exchange resins, and high HMF yields up to 70% were achieved. The effects of various reaction conditions like initial fructose concentration, catalyst concentration, water content in HFIP, temperature and influence of the catalyst particle size were evaluated. Up to 76% HMF yield was attained at optimized reaction conditions for high initial fructose concentration of 0.5 M (90 g/L). The ion-exchange resin can simply be recovered by filtration and reused several times. This reaction system with HFIP/water as solvent and the ion-exchange resin Lewatit K2420 as catalyst shows excellent performance for HMF synthesis.

Metal- and Reagent-Free Dehydrogenative Formal Benzyl-Aryl Cross-Coupling by Anodic Activation in 1,1,1,3,3,3-Hexafluoropropan-2-ol.

A selective dehydrogenative electrochemical functionalization of benzylic positions that employs 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) has been developed. The electrogenerated products are versatile intermediates for subsequent functionalizations as they act as masked benzylic cations that can be easily activated. Herein, we report a sustainable, scalable, and reagent- and metal-free dehydrogenative formal benzyl-aryl cross-coupling. Liberation of the benzylic cation was accomplished through the use of acid. Valuable diarylmethanes are accessible in the presence of aromatic nucleophiles. The direct application of electricity enables a safe and environmentally benign chemical transformation as oxidizers are replaced by electrons. A broad variety of different substrates and nucleophiles can be employed.

Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol.

Alzheimer's disease involves accumulation of senile plaques in which filamentous aggregates of amyloid beta (Aß) peptides are deposited. Recent studies demonstrate that oligomerization pathways of Aß peptides may be complicated. To understand the mechanisms of Aß(1-42) oligomer formation in more detail, we have established a method to produce (15)N-labeled Aß(1-42) suited for nuclear magnetic resonance (NMR) studies. For physicochemical studies, the starting protein material should be solely monomeric and all Aß aggregates must be removed. Here, we succeeded in fractionating a "precipitation-resistant" fraction of Aß(1-42) from an "aggregation-prone" fraction by high-performance liquid chromatography (HPLC), even from bacterially overexpressed Aß(1-42). However, both Aß(1-42) fractions after 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) treatment formed amyloid fibrils. This indicates that the "aggregation seed" was not completely monomerized during HFIP treatment. In addition, Aß(1-42) dissolved in HFIP was found to display a monomer-dimer equilibrium, as shown by two-dimensional (1)H-(15)N NMR. We demonstrated that the initial concentration of Aß during the HFIP pretreatment altered the kinetic profiles of Aß fibril formation in a thioflavin T fluorescence assay. The findings described here should ensure reproducible results when studying the Aß(1-42) peptide.

Membrane binding and insertion of the predicted transmembrane domain of human scramblase 1.

Human phospholipid scramblase 1 (SCR) was originally described as an intrinsic membrane protein catalyzing transbilayer phospholipid transfer in the absence of ATP. More recently, a role as a nuclear transcription factor has been proposed for SCR, either in addition or alternatively to its capacity to facilitate phospholipid flip-flop. Uncertainties exist as well from the structural point of view. A predicted α-helix (aa residues 288-306) located near the C-terminus has been alternatively proposed as a transmembrane domain, or as a protein core structural element. This paper explores the possibilities of the above helical segment as a transmembrane domain. To this aim two peptides were synthesized, one corresponding to the 19 α-helical residues, and one containing both the helix and the subsequent 12-residues constituting the C-end of the protein. The interaction of these peptides with lipid monolayers and bilayers was tested with Langmuir balance surface pressure measurements, proteoliposome reconstitution and analysis, differential scanning calorimetry, tests of bilayer permeability, and fluorescence confocal microscopy. Bilayers of 28 different lipid compositions were examined in which lipid electric charge, bilayer fluidity and lateral heterogeneity (domain formation) were varied. All the results concur in supporting the idea that the 288-306 peptide of SCR becomes membrane inserted in the presence of lipid bilayers. Thus, the data are in agreement with the possibility of SCR as an integral membrane protein, without rejecting alternative cell locations.