Fluorous Effect Research Articles

Multifunctional Nanocomposite Polymer-integrated Ca-doped CeO2 Electrolyte for Robust and High-rate All-solid-state Sodium-ion Batteries.

Due to the seamless interfaces between solid polymer electrolytes (SPEs) and electrode materials, SPEs-based all-solid-state sodium-ion batteries (ASSSIBs) are considered promising energy storage systems. However, the sluggish Na+ transport and uncontrollable Na dendrite propagation still hinder the practical application of SPEs-based ASSSIBs. Herein, Ca-doped CeO2 (Ca-CeO2) nanotube framework is synthesized and integrated with poly (ethylene oxide) methyl ether acrylate-perfluoropolyether copolymer (PEOA-PFPE), resulting in multifunctional solid nanocomposite electrolytes (namely SNEs, i.e., PEOA-PFPE/Ca-CeO2). Our investigations demonstrate that the fluorous effect incurred by the fluorine-containing PEOA-PFPE and the oxygen vacancy effect induced by the Ca-CeO2 framework could synergistically promote the dissociation of sodium salt, ultimately enhancing the Na+ mobility in SNEs. Besides, the resultant SNEs construct rapid Na+ transport channels and homogenize the Na deposition in SNEs/Na interface, which effectively prevents the Na dendrite growth. Furthermore, the assembled carbon-coated sodium vanadium phosphate (NVP@C)||PEOA-PFPE/Ca-CeO2||Na coin cell delivers impressive rate capability of 97.9 mA h g-1 at 2 C and outstanding cycling stability with capacity retention of 84.3% after 300 cycles at 1 C. This work illustrates that constructing multifunctional SNEs via incorporating functional inorganic frameworks into fluorine-containing SPEs could be a promising strategy for the commercialization of robust and high-performance ASSSIBs.

Betaketothioesters in organocatalysis: Harnessing nucleophilic reactivity, the fluorophobic effect, and expanding the substrate repertoire

The use of thioesters as nucleophiles marks a considerable change in organic synthesis. This new method, propelled by gentle enolization with minimal catalyst loading, results in enantiomeric excesses surpassing 95 % under ambient conditions, accomplishing total conversion in merely 6 h. Remarkably, this method eliminates the need for additional functional groups in nitroalkenes for efficient chirality transfer from the organocatalyst. The exceptional reactivity of thioesters, combined with their water tolerance, enables reactions utilizing the hydrophobic effect, resulting in reaction times as short as 15 min and products with slightly enhanced stereoselectivity compared to analogous reactions in dichloromethane. Additionally, reactions performed in perfluorinated solvents outpace their homogenous counterparts in organic solvents, delivering products in shorter time with comparable stereoselectivity. This work highlights the rare utilization of the fluorous effect in organocatalysis. Simple squaramides also exhibit remarkable catalytic activity in the reactions of beta-keto thioesters with alpha-bromo nitroalkenes. As little as 0.1 mol% of the catalyst leads to product formation with an 86 % yield (qNMR) and 93 % enantiomeric excess. Upscaling the reaction does not significantly affect the enantiomeric excess but leads to a slight decrease in yield from 82 % to 77 %. It has been demonstrated that thioesters react more rapidly than their ketoester counterparts, and the two-step reaction leading to dihydrofuran ring closure is entirely accomplished by extending the reaction time, eliminating the need for additional base. The examples presented here expand the range of substrates derived from carboxylic acid esters in catalytic reactions, suggesting the potential for the synthesis of challenging reactions in analogs of alkoxyl esters. Additional KS-DFT calculations shed more light on the reaction paths, rationalizing the observed stereochemical outcomes.

Fluorous-Directed Assembly of DNA Origami Nanostructures.

An orthogonal, noncovalent approach to direct the assembly of higher-order DNA origami nanostructures is described. By incorporating perfluorinated tags into the edges of DNA origami tiles we control their hierarchical assembly via fluorous-directed recognition. When we combine this approach with Watson-Crick base-pairing we form discrete dimeric constructs in significantly higher yield (8x) than when either molecular recognition method is used in isolation. This integrated "catch-and-latch" approach, which combines the strength and mobility of the fluorous effect with the specificity of base-pairing, provides an additional toolset for DNA nanotechnology, one that enables increased assembly efficiency while requiring significantly fewer DNA sequences. As a result, our integration of fluorous-directed assembly into origami systems represents a cheap, atom-efficient means to produce discrete superstructures.

A comparative photophysical study on the structurally related coumarin 102 and coumarin 153 dyes

Photophysical properties of two 7-aminocoumarin dyes, namely, coumarin 102 (C102) and coumarin 153 (C153), have been investigated in different aprotic solvents to understand their polarity dependent behaviors. Both the dyes have the same closed-ring amine (julolidyl) substituent at 7-th position of their 1,2-benzopyrone moiety, but differ in regard to their 4-CH3 and 4-CF3 substituents, respectively. For both the dyes, absorption and fluorescence spectra undergo red shift, peak energies of these transitions decrease and the Stokes’ shifts follow linear correlations with the increasing solvent polarity parameter Δf, as defined by Lippert-Mataga. While fluorescence quantum yield (Φf) and lifetime values (τf) of C102 dye undergo linear changes with Δf, both these parameters for C153 display quite unusual deviations from linearity in the lower polarity solvents. For C102, the estimated fluorescence decay rates (kf) are significantly higher than C153 dye. The nonradiative decay rates (knr) are also substantially higher for C102 dye than C153 in most of the solvents. Interestingly, while kf values for both the dyes change linearly with Δf, the knr values show complete linearity with Δf for C102 dye only, but these values for C153 dye show quite substantial enhancements and an unusual positive deviation from linearity in lower polarity solvent. Quantum chemical studies indicate that for C153 dye in lower polarity solvents, especially, there is a possible involvement of intersystem crossing process, which might induce an additional nonradiative channel (kadd-nr) for the dye. Further, though we could not obtain any direct evidence in the present study, yet it is felt that some kind of fluorous effect, as might be arising due to large negative charge density on bulky perfluomethyl group of C153 dye, can also introduce additional kadd-nr, specifically in the nonpolar solvents, for which further investigations are continuing in our group.

Novel amphiphilic fluorine-containing nanocarriers for oxygen self-sufficiency “AND” GSH depletion sequentially to enhance photodynamic therapy

In order to maximize the retention of the photodynamic therapy (PDT) efficacy, while avoiding the dilemma of hypoxia and high reducing substances in tumor tissue, fluoropolymers were synthesized in a simple and effective methods. Fluorous effect with good oxygen carrying capacity was endowed by the fluorine-containing section in fluoropolymers and the perfluorodecalin (PFD) together, the reaction site with GSH was provided by the disulfide bond, which enhanced PDT efficiency through the sequential “AND” logic gate design. Two kind of fluorine-containing nanocarriers (M-Ce6 and E-Ce6) were obtained by solvent evaporation or ultrasound emulsification with PFD, respectively. In vitro, both of them showed promising high ROS generation under photoirradiation. Benefiting by cavitation effects, E-Ce6 had a more significant statistical difference in cellular uptake. Furthermore, the cells incubating with E-Ce6 hardly were noticed that the hypoxia signal appeared under hypoxia, while reducing the intracellular GSH content by more than 15%. Through the sequential “AND” logic gate design, ROS production even under hypoxia and GSH conditions of E-Ce6 was also almost 1.5 times that of Ce6 under normoxia. Enhancing effect of E-Ce6 was 13.47 times and 6.85 times, while selectivity ratio reached 5.13 times and 4.81 times compared with Ce6 and M-Ce6. The two-pronged strategy showed a high potential for delivering the Ce6 to deep inside of cancer cells and killing it in the simulated tumor by PDT. These above results demonstrated the potential of E-Ce6, as oxygen self-sufficiency and GSH depletion nanocarriers for combined enhancement of photodynamic therapy.

Tuning of Ionic Liquid Crystal Properties by Combining Halogen Bonding and Fluorous Effect.

We report halogen-bonded complexes between 1-polyfluoroalkyl-3-alkylimidazolium iodides and mono-iodoperfluoroalkanes of different chain lengths or di-iodoperfluorooctane. 19 F NMR analyses revealed that the preferred stoichiometry between the donors and acceptors is 1 : 1 in the cases of the mono-iodoperfluoroalkanes, and 2 : 1 with di-iodoperfluorooctane, as a result of the monodentate behavior of the iodide anion (halogen bond acceptor). Single crystal X-ray diffraction analyses showed the presence of a perfluorinated superanion, which interdigitates with the cation fluorinated chains, favoring the formation of lamellar structures. All of the obtained supramolecular complexes exhibit enantiotropic liquid crystalline phases over a broad range of temperatures. Most of the obtained complexes show melting points lower than 100 °C, two of them being liquid at room temperature, thus representing a new family of fluorinated ionic liquid crystals.

A novel fluorous effect induced fluorescence sensor for Cu(ii) detection in the organic phase with high sensitivity

P(VDF–ATrFE) with excellent performance is employed as a fluorescent probe for Cu ion detection in the organic phase directly.

Theoretically predicting the feasibility of highly-fluorinated ethers as promising diluents for non-flammable concentrated electrolytes

The practical application of nonflammable highly salt-concentrated (HC) electrolyte is strongly desired for safe Li-ion batteries. Not only experimentalists but also theoreticians are extensively focusing on the dilution approach to address the limitations of HC electrolyte such as low ionic conductivity and high viscosity. This study suggests promising highly-fluorinated ethers to dilute the HC electrolyte based on non-flammable trimethyl phosphate (TMP) solvent. According to the quantum mechanical and molecular dynamics calculations, the fluorinated ether diluents showed a miscibility behavior in HC TMP-based electrolyte. While such miscibility behavior of the diluent with TMP solvent has been significantly enhanced by increasing its degree of fluorination, i.e., the “fluorous effect”, it is remarkable that the self-diffusion constant of Li+ and the ionic conductivity should be significantly improved by dilution with bis(1,1,2,2-tetrafluoro ethyl) ether (B2E) and bis(pentafluoro ethyl) ether (BPE) compared to other common hydrofluoroether diluents. In addition, the fluorinated-ether diluents have high ability to form a localized-concentrated electrolyte in HC TMP-based solution, leading to high expectation for the formation of a stable and a compact inorganic SEI film.

Fluorination Enhances NIR-II Fluorescence of Polymer Dots for Quantitative Brain Tumor Imaging.

Here, we describe a fluorination strategy for semiconducting polymers for the development of highly bright second near-infrared region (NIR-II) probes. Tetrafluorination yielded a fluorescence QY of 3.2 % for the polymer dots (Pdots), over a 3-fold enhancement compared to non-fluorinated counterparts. The fluorescence enhancement was attributable to a nanoscale fluorous effect in the Pdots that maintained the molecular planarity and minimized the structure distortion between the excited state and ground state, thus reducing the nonradiative relaxations. By performing through-skull and through-scalp imaging of the brain vasculature of live mice, we quantitatively analyzed the vascular morphology of transgenic brain tumors in terms of the vessel lengths, vessel branches, and vessel symmetry, which showed statistically significant differences from the wild type animals. The bright NIR-II Pdots obtained through fluorination chemistry provide insightful information for precise diagnosis of the malignancy of the brain tumor.

Fluorination Enhances NIR‐II Fluorescence of Polymer Dots for Quantitative Brain Tumor Imaging

AbstractHere, we describe a fluorination strategy for semiconducting polymers for the development of highly bright second near‐infrared region (NIR‐II) probes. Tetrafluorination yielded a fluorescence QY of 3.2 % for the polymer dots (Pdots), over a 3‐fold enhancement compared to non‐fluorinated counterparts. The fluorescence enhancement was attributable to a nanoscale fluorous effect in the Pdots that maintained the molecular planarity and minimized the structure distortion between the excited state and ground state, thus reducing the nonradiative relaxations. By performing through‐skull and through‐scalp imaging of the brain vasculature of live mice, we quantitatively analyzed the vascular morphology of transgenic brain tumors in terms of the vessel lengths, vessel branches, and vessel symmetry, which showed statistically significant differences from the wild type animals. The bright NIR‐II Pdots obtained through fluorination chemistry provide insightful information for precise diagnosis of the malignancy of the brain tumor.

Fluorinated peptide biomaterials.

Fluorinated compounds, while rarely used by nature, are emerging as fundamental ingredients in biomedical research, with applications in drug discovery, metabolomics, biospectroscopy, and, as the focus of this review, peptide/protein engineering. Leveraging the fluorous effect to direct peptide assembly has evolved an entirely new class of organofluorine building blocks from which unique and bioactive materials can be constructed. Here, we discuss three distinct peptide fluorination strategies used to design and induce peptide assembly into nano-, micro-, and macrosupramolecular states that potentiate high-ordered organization into material scaffolds. These fluorine-tailored peptide assemblies employ the unique fluorous environment to boost biofunctionality for a broad range of applications, from drug delivery to antibacterial coatings. This review provides foundational tactics for peptide fluorination and discusses the utility of these fluorous-directed hierarchical structures as material platforms in diverse biomedical applications.

Lithium Salt Distribution and Thermodynamics in Electrolytes Based on Short Perfluoropolyether-block-Poly(ethylene oxide) Copolymers

Wide-angle X-ray scattering (WAXS) was used to study the distribution of salt in short-chain disordered block copolymer electrolytes with concentration fluctuations on the length scale of 1 nm. The electrolytes were binary mixtures of lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) salt and a short block copolymer comprising perfluoroether (PFE) segments covalently bonded to ethylene oxide (EO) segments. We develop a method to analyze scattering data from mixtures of block copolymers and salt where salt distribution is not known beforehand, using a minimal number of adjustable parameters. The WAXS peak due to scattering from disordered concentration fluctuations is fit to a random phase approximation (RPA) model that includes a parameter to describe the partitioning of salt between the perfluoropolyether (PFPE)-rich and poly(ethylene oxide) (PEO)-rich concentration fluctuations. This method enables quantification of the salt distribution and the effective Flory–Huggins interaction parameter between polymer segments. We posit that attractive interactions between the TFSI– anion and PFPE (fluorous effect) drive some of the salt into the PFPE-rich fluctuations. On the other hand, the attractive interactions between Li+ and EO segments drive the remaining salt molecules into the PEO-rich fluctuations. We use WAXS to quantify LiTFSI partitioning between the PFE and EO segments in the block copolymer. The segregation between blocks, quantified by an effective Flory–Huggins interaction parameter between polymer segments, decreases with increasing salt concentration, behavior that is atypical for block copolymer electrolytes.

Reversible DNA micro-patterning using the fluorous effect.

We describe a new method for the immobilisation of DNA into defined patterns with sub-micron resolution, using the fluorous effect. The method is fully reversible via a simple solvent wash, allowing the patterning, regeneration and re-patterning of surfaces with no degradation in binding efficiency following multiple removal/attachment cycles of different DNA sequences.

A Convenient Access to a [2]Rotaxane Proton Shuttle by Using a Fluorous Ponytail

The properties of rotaxanes and their constituents, ring and axle, sometimes do not differ much from one another resulting in tedious workup. In the case of a rotaxane designed to shuttle protons across a biological membrane (3–4 nm), molecular weight, shape, and functional groups of axle and rotaxane are similar. But when the macrocyclic ring of the rotaxane carries a fluorous residue, the fluorous effect distinguishes the rotaxane from the axle because the latter carries no fluorine atoms. This concept has been exploited to synthesize a [2]rotaxane in which the macrocyclic ring is protonable and the axle contains a permanent positive charge. Upon protonation/deprotonation of the macrocycle, a shuttling process is induced, which can lead to the transport of protons.

Fluorine-rich planetary environments as possible habitats for life.

In polar aprotic organic solvents, fluorine might be an element of choice for life that uses selected fluorinated building blocks as monomers of choice for self-assembling of its catalytic polymers. Organofluorine compounds are extremely rare in the chemistry of life as we know it. Biomolecules, when fluorinated such as peptides or proteins, exhibit a “fluorous effect”, i.e., they are fluorophilic (neither hydrophilic nor lipophilic). Such polymers, capable of creating self-sorting assemblies, resist denaturation by organic solvents by exclusion of fluorocarbon side chains from the organic phase. Fluorous cores consist of a compact interior, which is shielded from the surrounding solvent. Thus, we can anticipate that fluorine-containing “teflon”-like or “non-sticking” building blocks might be monomers of choice for the synthesis of organized polymeric structures in fluorine-rich planetary environments. Although no fluorine-rich planetary environment is known, theoretical considerations might help us to define chemistries that might support life in such environments. For example, one scenario is that all molecular oxygen may be used up by oxidation reactions on a planetary surface and fluorine gas could be released from F-rich magma later in the history of a planetary body to result in a fluorine-rich planetary environment.

Fluorinated proteins: from design and synthesis to structure and stability.

Fluorine is all but absent from biology; however, it has proved to be a remarkably useful element with which to modulate the activity of biological molecules and to study their mechanism of action. Our laboratory's interest in incorporating fluorine into proteins was stimulated by the unusual physicochemical properties exhibited by perfluorinated small molecules. These include extreme chemical inertness and thermal stability, properties that have made them valuable as nonstick coatings and fire retardants. Fluorocarbons also exhibit an unusual propensity to phase segregation. This phenomenon, which has been termed the "fluorous effect", has been effectively exploited in organic synthesis to purify compounds from reaction mixtures by extracting fluorocarbon-tagged molecules into fluorocarbon solvents. As biochemists, we were curious to explore whether the unusual physicochemical properties of perfluorocarbons could be engineered into proteins. To do this, we developed a synthesis of a highly fluorinated amino acid, hexafluoroleucine, and designed a model 4-helix bundle protein, α4H, in which the hydrophobic core was packed exclusively with leucine. We then investigated the effects of repacking the hydrophobic core of α4H with various combinations of leucine and hexafluoroleucine. These initial studies demonstrated that fluorination is a general and effective strategy for enhancing the stability of proteins against chemical and thermal denaturation and proteolytic degradation. We had originally envisaged that the "fluorous interactions", postulated from the self-segregating properties of fluorous solvents, might be used to mediate specific protein-protein interactions orthogonal to those of natural proteins. However, various lines of evidence indicate that no special, favorable fluorine-fluorine interactions occur in the core of the fluorinated α4 protein. This makes it unlikely that fluorinated amino acids can be used to direct protein-protein interactions. More recent detailed thermodynamic and structural studies in our laboratory have uncovered the basis for the remarkably general ability of fluorinated side chains to stabilize protein structure. Crystal structures of α4H and its fluorinated analogues show that the fluorinated residues fit into the hydrophobic core with remarkably little perturbation to the structure. This is explained by the fact that fluorinated side chains, although larger, very closely preserve the shape of the hydrophobic amino acids they replace. Thus, an increase in buried hydrophobic surface area in the folded state is responsible for the additional thermodynamic stability of the fluorinated protein. Measurements of ΔG°, ΔH°, ΔS°, and ΔCp° for unfolding demonstrate that the "fluorous" stabilization of these protein arises from the hydrophobic effect in the same way that hydrophobic partitioning stabilizes natural proteins.

Evolution of fluorinated enzymes: An emerging trend for biocatalyst stabilization

Nature uses remarkably limited sets of chemistries in its repertoire, especially when compared to synthetic organic chemistry. This limits both the chemical and structural diversity that can ultimately be achieved with biocatalysis, unless the powers of chemical synthesis are merged with biological systems by integrating nonnatural synthetic chemistries into the protoplasma of living cells. Of particular interest, here is the fluorous effect that has recently established the potential to generate enzymes with an increased resistance toward both high temperature and organic solvents. For these reasons, we are witnessing a rapid development of efficient methodologies for the incorporation of fluorinated amino acids in protein synthesis, using both in vivo and in vitro strategies. In this review, we highlight relevant and trendsetting results in the design and engineering of stable fluorinated proteins and peptides along with whole‐cell biocatalysis as an economically attractive and convenient application with exclusive focus on industrial biocatalysis. Finally, we envision new strategies to improve current achievements and enable the field to progress far beyond the current state‐of‐the‐art.

The fluorous effect in biomolecular applications

From being a niche area only a few decades ago, fluorous chemistry has gained momentum and is, nowadays, a fervent area of research. It has brought forth, in fact, numerous applicative innovations that stretch among different fields: from catalysis to separation science, from supramolecular to materials and analytical chemistry. Recently, the unique features of perfluorinated compounds have reached the attention of the biochemists' audience. This tutorial review introduces the basic concepts of fluorous chemistry and illustrates its main biomolecular applications. Special attention has been given to fluorous microarrays and their combination with Mass-Spectroscopy (MS) techniques, to protein properties modification by the introduction of local fluorous domains, and to the most recent applications of (19)F-Magnetic Resonance Imaging ((19)F-MRI).

Role of intermolecular interactions involving organic fluorine in trifluoromethylated benzanilides

Trifluoromethylated benzanilides, containing C(sp3)–F bonds, have been synthesized and their crystal and molecular structures have been investigated to highlight the significance of weak intermolecular interactions associated with the presence of organic fluorine in a molecule. It is observed that the molecular conformation and packing characteristics are a delicate interplay amongst different intermolecular interactions, namely strong N–H⋯OC, weak C–H⋯OC, C–H⋯F–C, and C–H⋯π H-bonds, along with C–F⋯F–C and C–F⋯π intermolecular interactions in the solid state. All the isomers are associated with variations in crystal packing due to the presence of different supramolecular variants introduced by the presence of a trifluoromethyl group at the ortho, meta and para positions of the phenyl ring. Furthermore, a comparison of the experimental molecular conformation with that obtained from DFT theoretical calculations delineates the significant role of the trifluoromethyl group on the phenyl ring, which results in variations in conformational flexibility associated with the molecule. It has been observed that the –CF3group is associated with rotational disorder in some of the crystalline solids and the overall crystal structure is stabilized by a network of C(sp2)–H⋯F–C(sp3) intermolecular H-bonds and C–(sp3)F⋯F–C(sp3) contacts [the “fluorous effect”] in the crystalline lattice. It is also observed that there also exists a definite relationship between the acidity of the participating hydrogens with the hydrogen bonding characteristics of such weak C–H⋯F–C H-bonds in the crystal.

Disassembly via an environmentally friendly and efficient fluorous phase constructed with dendritic architectures

AbstractTraditionally the fluorous phase is generated with perfluorinated alkyl groups that are usually perfluorooctyl or longer and are bioaccummulative and biopersistent and therefore, are considered environmentally unfriendly. Here we report a new concept for the construction of the fluorous phase. This concept is based on the amplification of the fluorous effect with the help of dendritic architectures containing very short semifluorinated groups on their periphery. This new concept was demonstrated by the convergent synthesis of the first and second generation AB3 and AB2 benzyl ether dendrons functionalized on their periphery via catalytic nucleophilic addition of their phenolates to perfluoropropyl vinyl ether. The resulting dendrons are liquids. Their fluorous phase affinity was analyzed and demonstrated that the dendritic architecture amplifies the fluorous phase at a specific generation by the number of functional groups on the dendron periphery, and at different generations by increasing their generation number. Therefore, this concept is very efficient for the design and synthesis of new fluorous materials. In addition, by contrast with dendrons containing perfluoroalkyl groups on their periphery, the current dendrons mediate the disassembly of their parent building blocks but do not mediate the self‐assembly in a supramolecular architecture. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2498–2508, 2010