Fluorous Phase Research Articles

A Reduction-Sensitive Fluorous Fluorogenic Coumarin.

Fluorophores that are sensitive to their environment are useful tools for sensing chemical changes and probing biological systems. Here, we extend responsive fluorophores to the fluorous phase with the synthesis of a reduction-sensitive fluorous-soluble fluorogenic coumarin. We demonstrate that this fluorophore responds to various reducing agents, most notably glutathione, a key biological reductant. The fluorous solubility of this probe allows for its encapsulation into two different fluorous nanomaterials: perfluorocarbon nanoemulsions and fluorous core-shell micelles. The fluorogenic coumarin allows us to study how efficiently these vehicles protect the contents of their interior from the external environment. In the presence of glutathione, we observe different degrees of release for micelles and emulsions. This understanding will help guide future applications of fluorous nanomaterials as drug delivery vehicles.

Paramagnetic Fluorinated Nanoemulsions for in vivo F-19 MRI.

We aim to develop perfluorocarbon-based nanoemulsions with improved sensitivity for detection of inflammatory macrophages in situ using F-19 MRI. Towards this goal, we evaluate the feasibility of nanoemulsion formulation incorporating a metal chelate in the fluorous phase which shortens the F-19 longitudinal relaxation rate and image acquisition time. Perfluorinated linear polymers were conjugated to metal-binding tris-diketonate, blended with unconjugated polymers, and emulsified in water. Phospholipid-based surfactant was used to stabilize nanoemulsion and provide biocompatibility. Nanoemulsions were metalated with the addition of ferric salt to the buffer. Physical stability of surfactant and nanoemulsion was evaluated by mass spectrometry and dynamic light scattering measurements. Nanoemulsions were injected intravenously into a murine granuloma inflammation model, and in vivo19F/1H MRI at 11.7T was performed. We demonstrated stability and biocompatibility of lipid-based paramagnetic nanoemulsions. We investigated potential oxidation of lipid in the presence of metal chelate. As a proof of concept, we performed non-invasive monitoring of macrophage burden in a murine inflammation model following intravenous injection of nanoemulsion using in vivo F-19 MRI. Lipid-based nanoemulsion probes of perfluorocarbon synthesized with iron-binding fluorinated β-diketones can be formulated for intravenous delivery and inflammation detection in vivo.

Extraction Performance of a Fluorous Phosphate for Zr(IV) from HNO3 Solution: Comparison with Tri-n-Butyl Phosphate

ABSTRACTWe compare the extraction performance of new extractant, fluorous phosphate tris(4,4,5,5,6,6,7,7,7-nonafluoroheptyl) phosphate (TFP) in the fluorinated diluent perfluorohexane, for Zr(IV) with a conventional organic extractant, tri-n-butyl phosphate (TBP) in n-octane. It is surprising that fluorinating TBP to TFP improved the extraction performance, as normally fluorinating the hydrocarbon substituents on neutral extractants tends to decrease the extraction strength. We examined the origin of the superior extraction performance of TFP by analyzing the equilibrium of the chemical reaction during the extraction. The equilibrium reaction of Zr(IV) with TFP is , whereas that with TBP is . Phosphorus-31 nuclear magnetic resonance and infrared spectroscopy measurements of TFP and TBP showed similar electron densities at the phosphorus atom and vibration modes of the P=O group, implying similar coordination to Zr(IV). In addition, the concentrations of all components (Zr(IV), HNO3, and water) in the fluorous and organic phases after solvent extraction were evaluated by inductively coupled plasma-mass spectrometry, ion chromatography, and Karl-Fischer titration. The concentrations of water and HNO3 molecules in the fluorous phase become low during the Zr(NO3)4(TFP)3 extraction, indicating that water and HNO3 molecules do not preferentially interact with Zr(NO3)4(TFP)3 in contrast to Zr(NO3)4(TBP)2 in n-octane We speculate that the excellent performance originated from the stability of Zr(NO3)4(TFP)3 in the fluorous phase. Hence, TFP is expected to be used as an alternative extractant to TBP.

Fluorous-phase iron oxide nanoparticles as enhancers of acoustic droplet vaporization of perfluorocarbons with supra-physiologic boiling point

Perfluorocarbon emulsion nanodroplets containing iron oxide nanoparticles (IONPs) within their inner perfluorohexane (PFH) core were prepared to investigate potential use as an acoustically activatable ultrasound contrast agent, with the hypothesis that incorporation of IONPs into the fluorous phase of a liquid perfluorocarbon emulsion would potentiate acoustic vaporization. IONPs with an oleic acid (OA) hydrophobic coating were synthesized through chemical co-precipitation. To suspend IONP in PFH, OA was exchanged with perfluorononanoic acid (PFNA) via ligand exchange to yield fluorophilic PFNA-coated IONPs (PFNA-IONPs). Suspensions with various amounts of PFNA-IONPs (0–15% w/v) in PFH were emulsified in saline by sonication, using 5% (w/v) egg yolk phospholipid as an emulsifier. PFNA-IONPs were characterized with transmission electron microscopy (TEM), transmission electron cryomicroscopy (cryoTEM), and thermogravimetric analysis (TGA) with Fourier transform infrared spectroscopy (FTIR). IONP were between 5 and 10 nm in diameter as measured by electron microscopy, and hydrodynamic size of the PFH nanodroplets were 150 to 230 nm as measured by dynamic light scattering (DLS). Acoustic droplet vaporization of PFH nanodroplets (PFH-NDs) was induced using conversion pulses (100 cycle at 1.1 MHz and 50% duty cycle) provided by a focused ultrasound transducer, and formed microbubbles were imaged using a clinical ultrasound scanner. The acoustic pressure threshold needed for PFH-NDs vaporization decreased with increasing temperature and IONP content. PFH-NDs containing 5% w/v IONP converted to microbubbles at 42 °C at 2.18 MI, which is just above the exposure limits of 1.9 MI allowed by the FDA for clinical ultrasound scanners, whereas 10 and 15% emulsion vaporized at 1.87 and 1.24 MI, respectively. Furthermore, 5% IONP-loaded PFH-NDs injected intravenously into melanoma-bearing mice at a dose of 120 mg PFH/kg, converted into detectable microbubbles in vivo 5 h, but not shortly after injection, indicating that this technique detects NDs accumulated in tumors.

Fluorescent Recognition of Functional Secondary Amines in the Fluorous Phase

In a fluorous solvent (perfluorohexane, FC‐72), a perfluoroalkyl‐substituted 2‐hydroxy‐1‐naphthaldehyde (1) was found to show greatly enhanced fluorescence when treated with certain functional secondary amines but little fluorescence response was observed with unfunctional amines as well as functional primary and tertiary amines. The study of the reaction of 1 with 2‐methylamino ethanol (8) reveals a facile cyclocondensation of the aldehyde group of 1 with this 1,2‐amino alcohol to form a 5‐membered ring oxazolidine product which turns on the fluorescence. The reaction of 1 with the amino alcohol was found to be more favorable in the fluorous solvent than in a common organic solvent. The use of the fluorous phase‐based fluorescence measurement in this work provides a potentially more sensitive as well as selective method in amine sensing.

Fluorofluorescent Perylene Bisimides

Perfluorinated liquids can exhibit immiscibility with organic solvents and water, and provide orthogonal opportunities in chemistry. Examples of emissive dyes that display only fluorous phase solubility are limited, despite the many potential applications. Perylene bisimides are among the most versatile dyes and are known for their outstanding stability and high quantum yields. Herein, we report the synthesis of two new “fluorofluorescent” perylene bisimide dyes, designed to be soluble in the fluorous phases. These two dyes possess unique photophysical properties, including dramatic increases in fluorescence quantum yields when treated with Brønsted acids as well as aggregation in the fluorous phase.

Fluorescent Recognition of 1,3‐Diaminopropane in the Fluorous Phase – Greatly Enhanced Sensitivity and Selectivity

A 1,1′‐binaphthyl‐based dialdehyde, which is soluble in the fluorous phase, is synthesized. The fluorescence of this compound is greatly enhanced by 1,3‐diaminopropane (DAP) in perfluorohexane (FC‐72) but not by other amines and diamines. Thus, this compound can be used as a fluorescent sensor for the detection of the biologically important DAP at submicromolar concentrations. The selectivity and sensitivity of this fluorescent probe in this fluorous solvent are much greater than those in the common organic solvent dichloromethane.

Fluorescent Cyanine Dye J-Aggregates in the Fluorous Phase.

We present a perfluorocarbon-hydrocarbon amphiphilic cyanine dye that J-aggregates in fluorous solvent. J-Aggregation is a special type of fluorophore aggregation, affording enhanced photophysical properties. Cyanine dyes are excellent J-aggregators in water but, until now, cyanine J-aggregates have not been translated to nonaqueous media. The fluorous phase J-aggregate displays enhanced photostability and processability compared to analogous aqueous aggregates.

Fluorous-tag assisted synthesis of a glycosaminoglycan mimetic tetrasaccharide as a high-affinity FGF-2 and midkine ligand

Here, we present the preparation of a sulfated, fully protected tetrasaccharide derivative following the glycosaminoglycan (GAG)-related sequence GlcNAc-β(1 → 4)-Glc-β(1 → 3). The tetramer was efficiently assembled via an iterative glycosylation strategy using monosaccharide building blocks. A fluorous tag was attached at position 6 of the reducing end unit enabling the purification of reaction intermediates by simple fluorous solid phase extraction. Fluorescence polarization competition experiments revealed that the synthesized tetrasaccharide strongly interacts with two heparin-binding growth factors, midkine and FGF-2 (IC50 of 270 nM and 2.4 µM, respectively). Our data indicate that this type of oligosaccharide derivatives, displaying sulfates, hydrophobic protecting groups and a fluorinated tail can be considered as interesting GAG mimetics for the regulation of relevant carbohydrate-protein interactions.

Fluorous-Phase Approach to α-Hydroxytropolone Synthesis.

α-Hydroxytropolones (αHTs) are troponoids that demonstrate inhibition against an array of therapeutically significant targets, making them potential drug leads for several human diseases. We have utilized a recently discovered one-pot three-component oxidopyrylium cycloaddition in a solid-supported synthesis of αHTs. Though the procedure is time efficient and generates assay-ready molecules, the system suffers from low yields and an inability to perform reaction modifications on resin-bound intermediates. In order to combat these issues with the solid-phase platform, we incorporated fluorous tags into our synthetic route. Through the implementation of fluorous phase chemistry, we demonstrate a substantial increase in the overall yield of αHTs, as well as an ability to execute metal-catalyzed cross coupling and amide coupling on fluorous tagged intermediates. We also show that tagged molecules can be separated from nonfluorous impurities, and vice versa, by utilizing fluorous liquid-liquid and solid-phase extractions. Hence, these proof-of-principle investigations describe the viability of a fluorous phase approach to αHT synthesis and its potential to serve as a combinatorial technique to produce structurally diverse substrates.

Impact of the Long-Range Electronic Effect of a Fluorous Ponytail on Metal Coordination during Solvent Extraction.

With the need for a precise description of the long-range electronic effects of a perfloroalkyl chain (F-ponytail) grafted onto metal chelators, we studied in detail the effect of a spacer inserted between the polar complexing head and the F-ponytail, in relation to the metal coordination ability of the resulting molecules. The prepared molecules were then applied for the extraction of various metals from an aqueous phase into an organic phase, and the optimum spacer length could be estimated to be between three and four methylene units, according to the extraction conditions. The study also revealed the difficulty of modeling and anticipating the tiny energy differences involved in the extraction process and the importance in peculiar cases to go beyond only these studied inductive effects to understand better the factors that govern the stabilization of a metallic cation in a complex fluorous phase.

A Highly Fluorinated Chiral Aldehyde for Enantioselective Fluorescent Recognition in a Biphasic System.

A 1,1'-bi-2-naphthol (BINOL)-based aldehyde containing four perfluoroalkyl groups has been designed and synthesized. It shows enantioselective fluorescence enhancement at 420 nm when treated with the enantiomers of trans-1,2-diaminocyclohexane in an organic/fluorous biphasic system. The enantiomeric excess of the diamine in methanol can be linearly correlated with the emission intensity of of the aldehyde in perfluorohexane (FC-72). This is the first example to determine the enantiomeric composition of a chiral molecule by using a fluorescent sensor in a fluorous/organic biphasic system. The mechanism of the reaction was investigated by NMR spectroscopy and mass spectrometry.

Catalyst retention utilizing a novel fluorinated phosphonium ionic liquid in Heck reactions under fluorous biphasic conditions

A novel ionic liquid based on a highly fluorinated phosphonium cation was synthesized and its physicochemical properties were compared to its semi- and non-fluorinated analogue. The fluorinated ionic liquid was found to show a thermomorphic mixing behavior with organic solvents so that it could be applied as a substitute for volatile perfluorinated solvents in fluorous biphasic catalysis to achieve the recovery of perfluoro-tagged catalysts. Efficient immobilization of a perfluoro-tagged palladium catalyst in the fluorous ionic liquid phase was demonstrated for the Heck reaction as a model reaction of the widely applied Pd-catalysed CC coupling reactions. The reaction of iodobenzene and methyl acrylate resulted in 83% yield after 20 runs proofing the efficient immobilization in the fluorophilic ionic liquid.

Fluorous‐Phase‐Based Chiral Assay with Circular Dichroism Spectroscopy

A highly fluorinated molecular probe made of a salicylaldehyde derivative is designed and synthesized for the detection of chiral amines in the fluorous phase. When treated with various chiral amines in a fluorous solvent (perfluorohexyl ethanol), this probe shows intense CD signals at wavelengths greater than 400 nm, which has been used to determine the enantiomeric composition of chiral amines, amino alcohols, and amino acids. This is the first example of CD recognition of chiral compounds that is conducted in the fluorous phase. The approach could greatly reduce the undesired interference in the direct assay of asymmetric reactions and catalytic processes.

Ion Aggregation and R3N+-C(R)-H···NR3 Hydrogen Bonding in a Fluorous Phase.

Potentiometric selectivities show that in fluorous ion-selective electrode membranes the tetrabutylammonium ion binds to fluorophilic proton ionophores. For the ionophore bis[3-(perfluorooctyl)propyl](2,2,2-trifluoroethyl)amine, this type of interaction is confirmed by the effect of the ionophore on the ionic conductivity of perfluoro(perhydrophenanthrene) solutions of a fluorophilic NBu4+ salt. In this system, ion pairs, triple ions, and higher ionic aggregates dominate over single ions, and the ionophore increases the conductivity by favoring the formation of ion aggregates with a net charge. These observations are consistent with the formation of R3N+-C(R)-H···NR3 type hydrogen bonds between the nitrogen atom of the ionophore and the hydrogen atoms in the α position to the positively charged quaternary ammonium center of NBu4+. Similar interactions were observed in a number of crystalline phases. To date, observations of C-H···N type hydrogen bonds in liquid phases have been very few, and solution-phase N+-C-H···N type hydrogen bonds have not been reported previously. Interestingly, no interactions between NBu4+ and the more basic ionophore tridodecylamine were observed in conventional plasticized poly(vinyl chloride) membranes doped with the ionophore tridodecylamine, emphasizing the uniquely low polarity of fluorous phases.

Are fluorine-rich pharmaceuticals lost by partition into fluorous phases?

The recently developed technology of droplet microfluidics has demonstrated great potential for many applications such as biochemical assay, high throughput screening, cell culture, directed evolution, and chemical synthesis. Intrigued by its capabilities for miniaturization, flexible manipulation, rapid reagent mixing and high throughput experimentation and analysis, the pharmaceutical industry has begun to investigate droplet microfluidic implementation in medicinal and process chemistry. Segmented by an immiscible secondary phase, usually perfluorinated oil, aqueous or organic droplets serve as individual micro-reactors without suffering cross-contamination. As many drug molecules contain fluorines, it is necessary to investigate whether such compounds will be preferentially extracted into the fluorous phase via fluorophilic solvation, which could lead to erroneous analytical results. In this work, we chose drugs with up to 10 fluorines to probe their partition into perfluorodecalin (PFD) from a variety of organic solvents. A fast and straightforward MISER (Multiple Injections in a Single Experimental Run) LC–MS method was applied to measure the loss of drug after mixing with PFD. We found that no significant partition occurred, with the concentration of drugs in the ‘experimental’ group measured as ±10% of the ‘control’ group. The RSD% of multiple injections is <5%. The finding was further validated by the conventional LC–MS approach.

Supported Catalysts Useful in Ring-Closing Metathesis, Cross Metathesis, and Ring-Opening Metathesis Polymerization.

Ruthenium and molybdenum catalysts are widely used in synthesis of both small molecules and macromolecules. While major developments have led to new increasingly active catalysts that have high functional group compatibility and stereoselectivity, catalyst/product separation, catalyst recycling, and/or catalyst residue/product separation remain an issue in some applications of these catalysts. This review highlights some of the history of efforts to address these problems, first discussing the problem in the context of reactions like ring-closing metathesis and cross metathesis catalysis used in the synthesis of low molecular weight compounds. It then discusses in more detail progress in dealing with these issues in ring opening metathesis polymerization chemistry. Such approaches depend on a biphasic solid/liquid or liquid separation and can use either always biphasic or sometimes biphasic systems and approaches to this problem using insoluble inorganic supports, insoluble crosslinked polymeric organic supports, soluble polymeric supports, ionic liquids and fluorous phases are discussed.

Preparation of Fluorous Solvent-Dispersed Fe3O4 Nanocrystals: Role of Oxygen in Ligand Exchange.

Perfluorinated ligand-passivated Fe3O4 nanocrystals were prepared through a biphasic ligand exchange method. It was found that dissolved oxygen in the reaction media predominantly determined the degree of ligand exchange and the resultant dispersion property of nanocrystals in a fluorous solvent. X-ray photoelectron spectroscopic analyses revealed that dissolved oxygen molecules bind to the surface iron species of nanocrystals in competition with the carboxylate moiety of ligands during the exchange reaction, lowering the degree of ligand exchange and colloidal stability significantly. Reducing the oxygen content of the fluorous phase by N2 bubbling was found to result in a highly stable dispersion of phase-transferred Fe3O4 nanocrystals with a single-particle size distribution maintained for a few months.

Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging

Fluorine-19 magnetic resonance imaging (19F MRI) probes enable quantitative in vivo detection of cell therapies and inflammatory cells. Here, we describe the formulation of perfluorocarbon-based nanoemulsions with improved sensitivity for cellular MRI. Reduction of the 19F spin-lattice relaxation time (T1) enables rapid imaging and an improved signal-to-noise ratio, thereby improving cell detection sensitivity. We synthesized metal-binding β-diketones conjugated to linear perfluoropolyether (PFPE), formulated these fluorinated ligands as aqueous nanoemulsions, and then metalated them with various transition and lanthanide ions in the fluorous phase. Iron(III) tris-β-diketonate ('FETRIS') nanoemulsions with PFPE have low cytotoxicity (<20%) and superior MRI properties. Moreover, the 19F T1 can readily be reduced by an order of magnitude and tuned by stoichiometric modulation of the iron concentration. The resulting 19F MRI detection sensitivity is enhanced by 3-to-5 fold over previously used tracers at 11.7 T, and is predicted to increase by at least 8-fold at clinical field strength of 3 T.

An Analogue of Grubbs Third‐Generation Catalyst with Fluorophilic Pyridine Ligands: Fluorous/Organic Phase‐Transfer Activation of Ring‐Closing Alkene Metathesis

AbstractThe title catalyst (H2IMes)[3,5‐NC5H3(CH2CH2Rf8)2]2(Cl)2Ru(=CHPh) [H2IMes=1,3‐bis(2,4,6‐trimethylphenyl)‐4,5‐dihydroimidazol‐2‐ylidene, Rf8=(CF2)7CF3] was prepared from the fluorous pyridine 3,5‐NC5H3(CH2CH2Rf8)2 (2.1 equiv.) and the pyridine complex (H2IMes)(NC5H5)2(Cl)2Ru(=CHPh). 3,5‐NC5H3(CH2CH2Rf8)2 was synthesized by a Heck reaction of 3,5‐dibromopyridine and the fluorous alkene H2C=CHRf8 [2.4 equiv.; Pd(OAc)2 (cat.), n‐Bu4N+ Br−/NaOAc (2.0 equiv.)], followed by hydrogenation. The catalyst shows dramatic rate accelerations in the ring‐closing metatheses of α,ω‐dienes under fluorous/organic liquid/liquid biphasic conditions [e.g., perfluoro(methyldecalin)/CD2Cl2] relative to rates under monophasic organic conditions (e.g., CD2Cl2). These catalysts require initial dissociation of the pyridine ligands to generate the active species, which can either combine with an alkene (productive) or recombine with a pyridine (unproductive). In the case of (H2IMes)[3,5‐NC5H2(CH2CH2Rf8)2]2(Cl)2Ru(=CHPh), fluorophilic 3,5‐NC5H3(CH2CH2Rf8)2 transfers to the fluorous phase, in accord with its CF3C6F11/toluene partition coefficient [93.9:6.1 vs. 39.8:60.2 for (H2IMes)[3,5‐NC5H3(CH2CH2Rf8)2]2(Cl)2Ru(=CHPh)], which decreases the fraction of unproductive events.