Synthesis of novel lipophilic and/or fluorophilic ethers of perfluoro-tert-butyl alcohol, perfluoropinacol and hexafluoroacetone hydrate via a Mitsunobu reaction: Typical cases of ideal product separation

Fluorophilic ethers having the structure RC(CF₃)₂O(CH₂)₃C_nF_2n + 1 are obtained in high yields, when F-tert-butyl alcohol (R = CF₃), F-acetone hydrate (R = O(CH₂)₃C_nF_2n + 1), F-pinacol (R = C(CF₃)₂O(CH₂)₃C_nF_2n + 1) are reacted with 3-perfluoroalkyl-1-propanols (C_nF_2n + 1(CH₂)₃OH, n = 4, 6, 8, 10) in a Mitsunobu reaction (Ph₃P/DIAD [i-PrO₂CN = NCO₂Pr-i]/ether). The parent lipophilic ethers with the structure of (CF₃)₃CO(CH₂)₃C_nH_2n + 1 were prepared analogously using the corresponding fatty alcohols and F-tert-butyl alcohol. To achieve ideal separations, products were transferred to orthogonal phases relative to the other reaction components using fluorous extraction, fluorous solid-organic liquid filtration, or steam-distillation. Selected physical properties including melting and boiling point, together with fluorous partition coefficients of these ethers were determined and the figures obtained were qualitatively analyzed using relevant thermodynamic theories. Some of these ethers are liquids with rather low freezing points and are miscible with fluorocarbon solvents.     

Fluorophilic properties of (perfluorooctyl)ethyldimethylsilyl substituted and tetramethyl(perfluoroalkyl) substituted cyclopentadienes and their Ti(IV), Rh(III), and Rh(I) complexes

Fluorous partition coefficients in perfluorohexane/toluene system for 37 fluorinated silylcyclopentadienes, titanium(IV) complexes derived from them, perfluoroalkyl substituted tetramethylcyclopentadienes, and their Rh(III) and Rh(I) complexes were determined. Specific fluorophilicity and fluorousness according to Kiss and Rábai were calculated for each compound with the help of molecular volume computed with the Gaussian program. The results show relative unimportance of fluorine content parameter for fluorophilicity as shown by a rhodium(I) complex being fluorophilic at fluorine content as low as 46.3%. As expected, fluorophilicity increased with the fluorous ponytail length and ponytail number in series of similar compounds, whereas polar M-Cl bonds were decreasing it. Fluorophilicities of tetramethyl(perfluoroalkyl)cyclopentadiene tautomers varied considerably despite only small differences in molecular volume being found. Most of the compounds were prepared previously, several new silylcyclopentadienes and titanium(IV) silylcyclopentadienyl complexes are reported here for completion.     

Synthesis and characterization of fluorous (S)- and (R)-1-phenylethylamines that effect heat facilitated resolution of (±)-2-(8-carboxy-1-naphthylsulfinyl)benzoic acid via diastereomeric salt formation and study of their circular dichroism

Perfluoroalkyl- or nonafluoro-tert-butoxy-alkyl-substituted enantiopure amines having the structure PhCHCH₃(NR¹R²) [R¹ = H, CH₃; R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃; R¹ = R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃] are obtained in high yields, when (S)-(−)-1-phenylethylamine is reacted with readily accessible alkylating reagents or fluorous 2° amines (R¹ = H; R² = (CH₂)₃C₈F₁₇, (CH₂)₂OC(CF₃)₃) are methylated in a Leuckart-Wallach reaction. The solubility patterns of these novel chiral amines and their hydrochlorides are qualitatively described for a broad spectrum of solvents and the fluorous partition coefficients of the free bases are determined by GC. A novel method for the resolution of enantiomers is disclosed here, which involves the use a half-equivalent of the selected resolving agent in solvent water that displays low solubility for the crystalline diastereomeric salt(s) formed even at temperatures near to its boiling point. Compound (S)-(−)-PhCHCH₃[NH(CH₂)₃C₈F₁₇] is found to satisfy all the latter conditions and successfully used for the heat facilitated resolution of the title racemic acid. The circular dichroism (CD) spectra of six novel fluorous (S)-(−)-1-phenylethylamine derivatives are measured in ethanol, trifluoroethanol and hexafluoropropan-2-ol and discussed in detail.     

Fluorophilicity of alkyl and polyfluoroalkyl nicotinic acid ester prodrugs

The fluorophilicity of a series of hydrocarbon and fluorocarbon-functionalized nicotinic acid esters (nicotinates) is measured from their partitioning behavior (log K_p) in the biphasic solvent system of perfluoro(methylcyclohexane) (PFMC) and toluene. The chain length of the hydrocarbon or fluorocarbon alkyl group of the ester ranges from one to twelve carbon atoms. Knowledge of the fluorophilicity of these solutes is relevant to the design of these prodrugs for fluorocarbon-based drug delivery. The experimental log K_p values range from −1.72 to −3.40 for the hydrocarbon nicotinates and −1.64 to 0.13 for the fluorinated nicotinates, where only the prodrug with the longest fluorinated chain (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl nicotinic acid ester) partitions preferentially into the fluorinated phase (log K_p = 0.13). Predictions of the partition coefficients using solubility parameters calculated from group contribution techniques or molecular dynamics simulation are in reasonable agreement for the perhydrocarbon nicotinates and short chained perfluorinated nicotinates (≈0.3-39% deviation). Significant deviations from experimental partition coefficients (greater than 100%) are observed for the longest chain perfluoroalkyl nicotinates.     

Synthesis and solid state structure of fluorous probe molecules for fluorous separation applications

A series of colored hydrocarbon and fluorocarbon tagged 1-fluoro-4-alkylamino-anthraquinones and 1,4-bis-alkylamino-anthraquinone probe molecules were synthesized from a (fluorinated) alkyl amine and 1,4-difluoroanthraquinone to aid in the development of fluorous separation applications. The anthraquinones displayed stacking of the anthraquinone tricycle and interdigitation of the (fluorinated) alkyl chains in the solid state. Furthermore, intramolecular N-H?O hydrogen bonds forced the hydrocarbon and fluorocarbon tags into a conformation pointing away from the anthraquinone tricycle, with the angle of the tricycle plane normal and the main (fluorinated) alkyl vector ranging from 1° to 39°. Separation of the probe molecules on fluorous silica gel showed that the degree of fluorination of the probe molecules plays only a minor role with most eluents (e.g., hexane/ethyl acetate and methyl nonafluorobutyl ethers/ethyl acetate). However, toluene as eluent caused a pronounced separation by degree of fluorination for fluorocarbon, but not hydrocarbon tagged probe molecules on both silica gel and fluorous silica gel. These studies suggest that hydrocarbon and fluorocarbon tagged anthraquinones are useful probe molecules for the development of laboratory scale fluorous separation applications.     

Influence of fluorination on the characterization of fluorotelomer-based acrylate polymers by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry

The relative degree of fluorotelomer-based acrylate polymers (FTACPs) fluorination was demonstrated to influence the sample preparation protocol for matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry. A homologous series of FTACPs were synthesized from fluorotelomer and hydrocarbon acrylates of different chain lengths, which varied the ratio of perfluorinated to hydrogenated carbons (R_F/R_H). The solubility of FTACPs in tetrahydrofuran (THF) and chloroform was observed to decrease for highly fluorinated FTACPs (R_F/R_H > 0.5) promoting FTACP aggregation. No dependence on the degree of fluorination was observed for the solubility of FTACPs in the fluorinated solvents α,α,α-trifluorotoluene (TFT) or dichloropentafluoropropanes (HCFC-225). For FTACPs with a low degree of fluorination such as poly(8:2 FTAC-co-HDA) (R_F/R_H = 0.375), MALDI-ToF analysis was successful using a conventional sample preparation protocol with THF, and dithranol (Dith) matrix. Conversely, the poor solubility of the highly fluorinated poly(8:2 FTAC-co-BA) (R_F/R_H = 1.5) in THF resulted in mass discrimination. Several fluorinated sample preparation protocols were evaluated for poly(8:2 FTAC-co-BA) using TFT and HCFC-225, and decafluoroazobenzene (DFAB) or 2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB) matrices. The high volatility of HCFC-225 decreased FTACP pooling during solvent evaporation in comparison to the less volatile TFT, and improved the quantity of detectable signals. MALDI-ToF analysis of poly(8:2 FTAC-co-BA) in a 95:5 HCFC-225:methanol with DCTB being the best sample preparation protocol for highly fluorinated FTACPs in this study producing the highest number of observable signals. Employing a fluorinated sample preparation offers the capability of analyzing other highly fluorinated polymers that are not compatible with conventional sample preparations.     

New bis(fluoro-ponytailed) bipyridine ligands for Pd-catalyzed Heck reactions under fluorous biphasic catalysis condition

Three highly fluorinated bipyridine derivatives (4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy) {R_f=HCF₂(CF₂)₇ (1a), n-C₈F₁₇ (1b), n-C₁₀F₂₁ (1c)} have been synthesized using 4,4′-bis(BrCH₂)-2,2′-bpy and the corresponding fluorinated alkoxides. The fluorine contents of ligands 1a-c are 58.3, 59.8, and 62.3%, respectively. Despite its high fluorine content, the ligand 1a with a -CF₂H polar terminal group is more soluble in organic solvents. The ligand 1b is a white solid and is still moderately soluble in CH₂Cl₂. The ligand 1c has a high fluorophilicity, the partition ratio being 42:1 for the n-C₈F₁₈/CH₂Cl₂ system. The reaction of ligands 1a-c with [PdCl₂(CH₃CN)₂] results in the novel Pd complexes [PdCl₂(4,4′-bis-(R_fCH₂OCH₂)-2,2′-bpy)] where R_f=HCF₂(CF₂)₇ (2a), n-C₈F₁₇ (2b), n-C₁₀F₂₁ (2c), respectively. The Pd complex 2b is a pale yellow solid, and has been tested unsatisfactorily for FBC. Insoluble in organic solvents, the Pd complex 2c dissolves only in fluorinated solvents, for instance FC77, which is mainly n-C₈F₁₈. The novel Pd complex 2c has been tested as a catalyst in Heck reactions under a fluorous biphasic catalysis condition. It was found that the Pd complex 2c, after an easy separation, keeps its catalytic activity (>90% yield), even after seven runs. The TGA studies indicate that the Pd complexes 2a-c are stable up to 330 °C.