Heptadecafluorooctanesulfonic acid (C8F17SO3H) catalyzed intramolecular hydroamination of olefinic sulfonamides in fluorous biphase system (FBS)

A practical, efficient, and environmentally benign intramolecular hydroamination of olefinic sulfonamides was carried out in fluorous biphase system (FBS) using commercially available heptadecafluorooctanesulfonic acid (C₈F₁₇SO₃H) as a catalyst and perfluorodecaline (C₁₀F₁₈, cis- and trans- mixture) as a fluorous solvent to produce the corresponding cyclic products in good yields. The Brønsted acid of C₈F₁₇SO₃H is easily recovered and recycled at least five times.     

A two‐step strategy to visually identify molecularly imprinted polymers for tagged proteins

A practical and relatively simple method to identify molecularly imprinted polymers capable of binding proteins via the molecular tagging (epitope‐like) approach has been developed. In our two‐step method, we first challenge a previously obtained anti‐tag molecularly imprinted polymer with a small molecule including the said tag of choice (a biotin derivative as shown here or other) connected to a linker bound to a second biotin moiety. An avidin molecule partially decorated with fluorescent labels is then allowed to bind the available biotin derivative associated with the polymer matrix. At the end of this simple process, and after washing off all the low‐affinity binding molecules from the polymer matrix, only suitable molecularly imprinted polymers binding avidin through its previously acquired small molecule tag (or epitope‐like probe, in a general case) will remain fluorescent. For confirmation, we tested the selective performance of the anti‐biotin molecularly imprinted polymer binding it to biotinylated alkaline phosphatase. Residual chemical activity of the enzyme on the molecularly imprinted polymer solid support was observed. In all cases, the corresponding nonimprinted polymer controls were inactive.     

Conformational dependence of tag induced intramolecular STM contrast in hexaphenylbenzene molecules

Chemically tagged hexaphenylbenzene molecules physisorbed on Au(1 1 1) surface display their tag differently under STM as compared to their physisorption on a Cu(1 1 1) surface. Our STM findings complemented by First Principles and Quantum Chemistry calculations have attributed this difference to two different conformations adopted by these molecules on Au(1 1 1) in comparison to its one conformation on Cu(1 1 1). The demonstration of the sensitivity of the tag to its electronic or chemical environment would have important implications in designing single molecule machinery where the motion of the molecule is to be discerned by tracking its tag induced intramolecular STM contrast.     

Evaluation of the hydrophobicity of perfluoroalkyl chains in amphiphilic compounds that are incorporated into cell membrane

Incubation of animal cells in the presence of amphiphilic glycosides having a lactoside residue (hydrophilic moiety) and various kinds of perfluoroalkyl chain (hydrophobic moiety) resulted to glycosylation of the saccharide chain by cellular enzymes and afforded glycolipid-like compounds. The amounts of amphiphilic glycoside and glycolipid-like compounds found in the cell and culture medium fractions, respectively, varied depending on the fluorine content of the perfluoroalkyl chain. To investigate further, the hydrophobicity of the perfluoroalkyl chain was estimated from the critical micelle concentration values and was found to be 1.5 times larger in hydrophobicity than the hydrocarbon chain [CF₂ = 1.5CH₂]. Liposomes resembling cells in size were also prepared and the amphiphilic glycosides were introduced. Results showed a positive correlation between hydrophobicity and localization of amphiphilic glycoside into liposomes. The amount of amphiphilic glycosides localized in liposomes increased with increasing hydrophobicity that is attributed mainly to the fluorine content of the aglycon. In spite of the low affinity of fluorous chain for hydrocarbon chain, the amphiphilic fluorous compounds showed high affinity for cell membrane that is composed of amphiphilic phospholipids.     

Fluorous chemistry in Pittsburgh: 1996-2008

The article summarizes a lecture presented at the American Chemical Society Symposium for the 2008 Award for Creative Work in Fluorine Chemistry on 7 April 2008. A high level, historical overview of work in the fluorous field at the University of Pittsburgh is presented.     

Extraction of perfluorinated compounds from food matrices using fluorous solvent partitioning

Perfluorinated compounds (PFCs) such as perfluorooctane sulfonic acid (PFOS) have emerged as a new class of global environmental pollutant; they bioaccumulate and are persistent in the environment and in wildlife. Fluorine-fluorine interactions have been investigated as a means to isolate PFCs for mass spectrometric quantification. A novel sample extraction and cleanup procedure has been developed for fat-containing samples based on fluorous liquid-liquid extraction (F-LLE) in a triphasic solvent system consisting of hybrid:fluorous:organic solvent (trifluoroethanol:perfluorohexane/dichloromethane-saturated with water). This system partially separates fluorous from non-fluorous compounds, allowing removal of co-extractants, which had previously resulted in liquid chromatography mass spectrometry (LC-MS/MS) peak suppression preventing low-level detection of PFCs. The developed F-LLE was coupled with an existing extraction protocol allowing the limits of detection of PFCs to be lowered an order of magnitude for high fat samples. The developed workflow was used to show the absence of a range of eleven PFCs in nine UK and one Irish cheese samples. This representative application demonstrates a new application of fluorous-organic extraction in sample cleanup for measurement of fluorinated analytes in food, environment and broader analytical chemistry.     

Greener fluorous chemistry: Convenient preparation of new types of ‘CF3-rich’ secondary alkyl mesylates and their use for the synthesis of azides, amines, imidazoles and imidazolium salts

2,2,2-Trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and nonafluoro-tert-butyl alcohol were used as precursors for the preparation of the appropriate bis(polyfluoroalkoxymethyl)carbinols [(R_FHOCH₂)₂CHOH, 1a-c, R_FH = (a) CF₃CH₂, (b) (CF₃)₂CH, and (c) (CF₃)₃C] and the corresponding mesylates [(R_FHOCH₂)₂CHOSO₂CH₃, 2a-c]. This novel design paradigm is introduced to eliminate the persistence and bioaccumulation problems of fluorous chemistry, which are associated with the use of longer linear perfluoroalkyl groups (e.g. R_fn ≥ n-C₈F₁₇, n-C₇F₁₅). Secondary mesylates 2a,b and the primary tosylate [(CF₃)₃COCH₂CH₂OTs, 2d] displayed acceptable reactivity towards azide and imidazole nucleophiles to allow the syntheses of novel fluorous azides, which on hydrogenolysis with H₂/Pd-C offered fluorous amines [(R_FHOCH₂)₂CHNH₂, 8a,b], and 1-(polyfluoroalkyl)imidazoles (5a,b,d), respectively, while 2c showed no reactivity due to steric hindrance. The reaction of 8a,b with formaline, glyoxal and hydrochloric acid gave symmetrical 1,3-dialkylated imidazolium chlorides (9a,b), while 5a,b,d were effectively alkylated using n-C₈F₁₇(CH₂)₃I, methyl iodide, 2-bromoethanol, and 2d to yield the corresponding 1,3-dialkylimidazolium iodides, bromides, and tosylates (7aa-ec). Some physical properties of new compounds including mp, bp and solubility patterns were also analyzed; and the fluorophilicity values of 1a-c, and 2a-c were experimentally determined by GC and/or ¹⁹F NMR spectroscopy.     

Syntheses of fluorous quaternary ammonium salts and their application as phase transfer catalysts for halide substitution reactions in extremely nonpolar fluorous solvents

Perfluoromethyldecalin solutions of the fluorous alkyl halides R_f8(CH₂)_mX (m=2, 3; X=Cl, I) are inert toward aqueous NaCl, KI, KCN, and NaOAc. However, substitution occurs at 100 °C in the presence of 10 mol % of the fluorous ammonium salts (R_f8(CH₂)₂)(R_f8(CH₂)₅)₃N⁺ I⁻ (1) or (R_f8(CH₂)₃)₄N⁺ Br⁻ (2) (10 mol %), which are fully or partially soluble in perfluoromethyldecalin under these conditions. Stoichiometric reactions of (a) 1 and R_f8(CH₂)₃Br, and (b) 2 and R_f8(CH₂)₂I are conducted in perfluoromethyldecalin at 100 °C, and yield the same R_f8(CH₂)_mI/R_f8(CH₂)_mBr equilibrium ratio (60-65:40-35). This shows that ionic displacements can take place in extremely nonpolar fluorous phases, and suggests a classical phase transfer mechanism for the catalyzed reactions. Interestingly, the non-fluorous ammonium salt mixture CH₃(CH₃(CH₂)_m)₃N⁺ Cl⁻ (3, Aliquat^® 336; m=2:1 7/9) also catalyzes halide substitutions, but under triphasic conditions with 3 suspended between the lower fluorous and upper aqueous layers. NMR experiments establish very low solubilities in both phases, suggesting interfacial catalysis.     

New axially dissymmetric ligand recoverable with fluorous solvent

Axially dissymmetric ligands with perfluoroalkyl groups, (Ra)-2,2′-bis[(R)-1-hydroxy-1H-perfluorooctyl]biphenyl [(Ra)-(R)₂-1c] and its enantiomer, have been synthesized successfully by the coupling reaction of the corresponding aryl bromide using Ni(COD)₂. These ligands showed much higher asymmetric induction in the reaction of various aldehydes with diethylzinc than the trifluoromethyl (1a) or pentafluoroethyl (1b) analogues. Furthermore, 1c was recovered quantitatively by extraction with a fluorous solvent from the reaction mixture due to its high fluorine content. The recovered ligand 1c was pure enough to be reused without purification. The efficiency of 1c as the chiral ligand was not decreased at all even after seven times recycling.     

Protein adsorption drastically reduces surface‐enhanced Raman signal of dye molecules

There is an increasing interest in developing surface enhancement Raman spectroscopy methods for intracellular biomolecule and for in vitro protein detection that involve dye or protein–dye conjugates. In this work, we have demonstrated that protein adsorption on silver nanoparticle (AgNP) can significantly attenuate the surface‐enhanced Raman spectroscopy (SERS) signal of dye molecules in both protein/dye mixtures and protein/dye conjugates. SERS spectra of 12 protein/dye mixtures were acquired using 4 proteins [bovine serum albumin (BSA), lysozyme, trypsin, and concanavalin A] and three dyes [Rhodamine 6G, adenine, and fluorescein isothiocyanate (FITC)]. Besides the protein/dye mixtures, spectra were also obtained for the free dyes and four FITC‐conjugated proteins. While no SERS signal was observed in protein/FITC mixtures or conjugates, a significantly reduced SERS intensity (up to 3 orders of magnitude) was observed for both R6G and adenine in their respective protein mixtures. Quantitative estimation of the number of dye molecules absorbed onto AgNP implied that the degree of R6G SERS signal reduction in the R6G/BSA sample is 2 to 3 orders of magnitude higher than what could be accounted for by the difference in the amount of the absorbed dyes. This finding has significant implications for both intracellular SERS analyses and in vitro protein detection using SERS tagging strategies that rely on Raman dyes as reporter molecules. Copyright © 2009 John Wiley & Sons, Ltd.