- Diversity-Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp3)?C(sp3) Cross-Coupling Fluoroalkylation
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Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a low-cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross-coupling of two alkyl halides. Results with 1-bromo-1-fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp3)-C(sp3) cross-coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional-group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first-order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate-determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.
- Sheng, Jie,Ni, Hui-Qi,Ni, Shan-Xiu,He, Yan,Cui, Ru,Liao, Guang-Xu,Bian, Kang-Jie,Wu, Bing-Bing,Wang, Xi-Sheng
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supporting information
p. 15020 - 15027
(2021/06/11)
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- A Series of Deoxyfluorination Reagents Featuring OCF2Functional Groups
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Research on perfluoroalkyl ether carboxylic acids (PFECAs) as alternatives for perfluoroalkyl substances continues with the goal of protecting the environment. However, very little is known about the utilization of decomposition products of PFECAs. We report herein a new series of deoxyfluorination reagents featuring OCF2 functional groups derived from certain PFECAs. Alkyl fluorides were generated from various alcohols in ≤97% yield by these novel reagents. The mechanistic experiment verified in situ generation of carbonic difluoride (COF2).
- Cao, Wei,Chen, Qing-Yun,Guo, Yong,Su, Zhaoben,Wu, Chengying,Zhao, Shiyu
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supporting information
(2020/11/03)
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- Copper-Catalyzed Regioselective Hydroalkylation of 1,3-Dienes with Alkyl Fluorides and Grignard Reagents
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Copper complexes generated in situ from CuCl2, alkyl Grignard reagents, and 1,3-dienes play important roles as catalytic active species for the 1,2-hydroalkylation of 1,3-dienes by alkyl fluorides through C-F bond cleavage. The alkyl group is introduced to an internal carbon atom of the 1,3-diene regioselectively, thus giving rise to the branched terminal alkene product. Making the switch: A copper-hydride species, generated by the treatment of a copper salt with alkyl Grignard reagents, catalyzes the 1,2-hydroalkylation of 1,3-dienes by alkyl fluorides and Grignard reagents. The alkyl group of the alkyl fluoride is selectively introduced to an internal carbon atom of the 1,3-diene and the Grignard reagent acts as hydride source to give the branched terminal alkene, even in the presence of alkenes and alkynes.
- Iwasaki, Takanori,Shimizu, Ryohei,Imanishi, Reiko,Kuniyasu, Hitoshi,Kambe, Nobuaki
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supporting information
p. 9347 - 9350
(2015/08/06)
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- Mild copper-catalyzed fluorination of alkyl triflates with potassium fluoride
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A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45°C using 2 mol% of the copper catalyst. With 10 mol% of the catalyst, full conversion can be achieved in less than 10 minutes at 45°C, and thus makes this procedure potentially suited for the preparation of 18F-labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase-transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).
- Dang, Hester,Mailig, Melrose,Lalic, Gojko
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supporting information
p. 6473 - 6476
(2014/06/24)
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- Ionic liquids as recyclable solvents for diethylaminosulfur trifluoride (DAST) mediated fluorination of alcohols and carbonyl compounds
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The first simple and efficient method for the synthesis of mono and gem-difluorinated molecules using [C8mim][PF6] ionic liquid as a recyclable solvent medium with diethylaminosulfur trifluoride (DAST) as the fluorinating reagent, is reported.
- Das, Saibal,Chandrasekhar, Srivari,Yadav, Jhillu Singh,Grée, René
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p. 5305 - 5307
(2008/02/10)
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- 1,1,3,3,3-Pentafluoropropene secondary amine adducts new selective fluorinating agents
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Addition of secondary amine SA (dimethylamine DMA, diethylamine DEA, pyrrolidine Pyr, piperidine Pip, morpholine Mor) to pentafluoropropene PFP gives rise to generation of mixtures of two products (1-dialkylamine-1,3,3,3-tetrafluoropropene and N,N-dialkyl-1,1,3,3,3-pentafluoropropylamine) in different ratios. Those reaction mixtures, however, were found to be efficient fluorinating agents replacing hydroxyl groups in alcohols into fluorine. In general, they react with alcohols yielding corresponding fluorides, equimolar amounts of appropriate 3,3,3-trifluoropropionamide and hydrogen fluoride. Aliphatic primary alcohols including octanol and benzylic alcohol yield only alkyl fluorides. The secondary and tertiary alcohols, beside the desired fluorides, give usually considerably amount of alkenes.
- Koroniak, Henryk,Walkowiak, Justyna,Grys, Krzysztof,Rajchel, Andrzej,Alty, Adam,Du Boisson, Rick
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p. 1245 - 1251
(2008/09/20)
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- A novel fluorinated erythromycin antibiotic
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A novel fluorinated erythromycin (16-fluoroerythromycin A) has been produced by Saccharopolyspora erythraea ERMD1, using precursor-directed biosynthesis. The Royal Society of Chemistry 2005.
- Goss, Rebecca J. M.,Hong, Hui
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p. 3983 - 3985
(2007/10/03)
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- Fluorination with aminosulfur trifluorides
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A fluorination method of oxygen and halogen sites with diaryl-, dialkoxyalkyl-, alkylalkoxyalkyl-, arylalkoxyalkyl- and cyclic aminosulfur trifluorides fluorinating reagents is disclosed.
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- 1,1,2,2-Tetrafluoroethyl-N,N-dimethylamine: A new selective fluorinating agent
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The title compound has been prepared in 96-98% yield by the reaction of tetrafluoroethylene and dimethylamine. 1,1,2,2-Tetrafluoroethyl-N,N-dimethylamine (1) is found to be an effective reagent for the conversion of alcohols into alkyl fluorides. Reaction of 1 and primary alcohols proceeds with high yield formation of the corresponding alkyl fluorides at elevated temperature. However, the reaction of secondary and tertiary alcohols rapidly takes place at 0-10°C, producing corresponding alkyl fluorides as major product along with some olefins.
- Petrov,Swearingen,Hong,Chris Petersen
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- Fluorination with aminosulfur trifluorides
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A fluorination method of oxygen and halogen sites with diaryl-, dialkoxyalkyl-, alkylalkoxyalkyl-, arylalkoxyalkyl- and cyclic aminosulfur trifluorides fluorinating reagents is disclosed.
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- Rearrangement and double fluorination in the deiodinative fluorination of neopentyl iodide with xenon difluoride
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Alkyl iodides give products from the neopentyl rearrangement on reaction with xenon difluoride. Neopentyl iodide performs a double rearrangement and yields a gem-difluoro product, 2,2-difluoro-3-methylbutane. Studies of the mechanism show that an alkene intermediate is involved in the double rearrangement process. Alkenes can be substituted as substrates in reaction with xenon difluoride-iodine to give gem-difluoro products. 13C Labeling verifies the skeletal rearrangement process.
- Patrick, Timothy B.,Zhang, Likang,Li, Quinhua
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- Bis(2-methoxyethyl)aminosulfur trifluoride: A new broad-spectrum deoxofluorinating agent with enhanced thermal stability
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Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is effective for the conversion of alcohols to alkyl fluorides, aldehydes/ketones to the corresponding gem-difluorides and also for the transformation of carboxylic acids to their trifluoromethyl derivatives; it is a less thermally sensitive, broader-spectrum alternative to the traditional dialkylaminosulfur trifluoride (DAST) deoxofluorination reagents.
- Lal, Gauri S.,Fez, Guido P.,Pesaresi, Reno J.,Prozonic, Frank M.
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p. 215 - 216
(2007/10/03)
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- Bis(2-methoxyethyl)aminosulfur trifluoride: A new broad-spectrum deoxofluorinating agent with enhanced thermal stability
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Bis(2-methoxyethyl)aminosulfur trifluoride, (CH3OCH2CH2)2NSF3 (Deoxo-Fluor reagent), is a new deoxofluorinating agent that is much more thermally stable than DAST (C2H5)2NSF3 and its congeners. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes/ketones to the corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some cases, superior performance compared to DAST. The enhanced stability is rationalized on the basis of conformational rigidity imposed by a coordination of the alkoxy groups with the electron-deficient sulfur atom of the trifluoride.
- Lal, Gauri S.,Pez, Guido P.,Pesaresi, Reno J.,Prozonic, Frank M.,Cheng, Hansong
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p. 7048 - 7054
(2007/10/03)
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- Halogen-exchange reactions between alkyl fluorides and boron trihalides or tetrahalides. A convenient synthesis of alkyl halides from alkyl fluorides
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A simple and effective method for converting fluoroalkanes to their corresponding chloro-, bromo- and iodo-alkanes using commercially available boron trihalides and titanium tetrahalides is described. - Keywords: Halogen-exchange reactions; Alkyl fluorides; Boron trihalides; Titanium tetrahalides; NMR spectroscopy; Mass spectrometry
- Namavari, Mohammad,Satyamurthy, N.,Barrio, Jorge R.
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- Facile Transformation of β-D-Ribofuranosyl Purines and Pyrimidines into Their Respective 3'-Deoxy-threo-pentofuranosyl Nucleosides
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Practical syntheses of 3'-deoxy-β-D-threo-pentofuranosyl-uracil, -cytosine, -adenine, and -guanine (3U, C, A, G) from the corresponding ribonucleosides by two one-pot reactions with readily accessible reagents are described.The key reactions are the selective 3'-O-methanesulphonylations of the ribonucleosides, the deoxygenative -hydride shift of the methanesulphonates, and the reduction of in situ generated 3'-deoxy-2'-keto nucleosides therefrom.
- Kawana, Masajiro,Nishikawa, Masahiro,Yamasaki, Noritsugu,Kuzuhara,Hiroyoshi
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p. 1593 - 1596
(2007/10/02)
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- Le formamide, un substitut de l'eau dans les reactions d'echange chlore-fluor par transfert de phase solide-liquide
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The fluoride-chloride exchange reaction RCl+KF -> RF+KCl catalysed by ammonium salts, was found to take place in presence of formamide in place of water.The results, depending of RCl are discussed in this paper.
- Escoula, Brigitte,Rico, Isabelle,Lattes, Armand
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p. 256 - 259
(2007/10/02)
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- SYNTHESIS OF ALKYL HALIDES UNDER NEUTRAL CONDITIONS
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Primary and secondary alcohols are efficiently converted to the corresponding alkyl halides under neutral conditions.
- Munyemana, Francois,Frisque-Hesbain, Anne-Marie,Devos, Alain,Ghosez, Leon
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p. 3077 - 3080
(2007/10/02)
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- PREPARATION OF MONOFLUOROCARBOXYLIC ACIDS USING N,N-DIETHYL-1,1,2,3,3,3-HEXAFLUOROPROPYLAMINE
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A method is outlined for the preparation of monofluorocarboxylic acids using Ishikawa's reagent, (C2H5)2NCF2CHFCF3 (PPDA), directly from hydroxyesters, or indirectly from monofluorinated alkylbenzenes, followed by the oxidation of the phenyl ring to a carboxylic acid.The chiral fluorocarboxylic acids, (2S) and (2R)-3-fluoro-2-methylpropionates (>99percent ee) and (2S)-2-fluoropropionic acid (55percent ee) are prepared as are 3-fluoropropionate and 4-fluorobutyrate.
- O'Hagan, D.
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p. 371 - 378
(2007/10/02)
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- Silver Fluoride Supported on Calcium Fluoride. Improved Fluorination and Halofluorination Reactions
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Silver fluoride dispersed on the surface of calcium fluoride shows improved fluoride nucleophilicity for halogen exchange and addition to alkenes.
- Ando, Takashi,Cork, David G.,Fujita, Mitsue,Kimura, Takahide,Tatsuno, Toshio
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p. 1877 - 1878
(2007/10/02)
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- LE FORMAMIDE, UN SUBSTITUT DE L'EAU XVI 1: REACTIONS D'ECHANGE CHLORE-FLUOR EN TRANSFERT DE PHASE SOLIDE-LIQUIDE
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The chloride-fluoride exchange reaction, RCl+KF -> RF+KCl, catalised by ammonium salts, was found to take place in the presence of formamide when this is used as a replacement for water.The experimental results and their dependence on RCl are discussed in this communication.
- Escoula, B.,Rico, I.,Lattes, A.
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p. 487 - 494
(2007/10/02)
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- A NEW SYNTHESIS OF ALKYL FLUORIDES
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Reduction of α-fluorosulfides with sodium in alcohol results in the formation of fluoroalkanes.
- Purrington, Suzanne T.,Pittman, James H.
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p. 6851 - 6852
(2007/10/02)
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- Reaction of SF4 with alcohols: preparation of 2-(fluoromethyl) furan and 2-fluoro-1-phenylethane
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The fluorination of (2-furyl)methanol and 2-phenylethanol with sulfur tetrafluoride is described. The reactions were carried out in glass tubes at -50°C in the presence of triethylamine or pyridine in dichloromethane or cyclohexane solution. The products,
- Janzen, Alexander F.,Marat, Ronald Kirk
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p. 205 - 208
(2007/10/02)
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- Use of Polyethylene Glycol in the Synthesis of Alkyl Fluorides from Alkyl Sulfonates
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In the synthesis of monofluorinated organic compounds, the reaction of potassium fluoride with mesylates and tosylates of alcohols affords fluoro derivatives when polyethylene glycol 400 is used as solvent and catalyst.The limitation of this reaction is the solvolysis of the leaving group by the solvent; the phenomenon is controlled by the degree of steric hindrance around the reaction centre.
- Badone, Domenico,Jommi, Giancarlo,Pagliarin, Roberto,Tavecchia, Paolo
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p. 920 - 921
(2007/10/02)
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- Replecement of the carboxylic acid function with fluorine
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Replacement of a carbonyl function by fluorine, fluorodecarboxylation, is a new process that can be accomplished by the reaction of alkanoic acids with xenon difluoride.Primary, tertiary, and benzylic acids perform best in the reaction, which is conducted at room temperature in methylene chloride or chloroform solution.A reaction mechanism is proposed in which the acid is initially converted to a fluoroxenon ester, RCO2XeF.The esters of the primary and secondary acids react by nucleophilic displacement by fluoride, as evidenced by incorporation of 18F- and no reactions common to free radicals or carbocations.The esters of the tertiary and benzylic acids react by converting to free radicals that can be further oxidized to carbocations.Thus incorporation of 18F- and racemization are observed with α-methoxy-α-trifluoromethylphenylacetic acid.Hydroxyl and amino functions inhibit the reaction.Aromatic and vinylic acids do not react.
- Patrick, Timothy B.,Johri, Kamalesh K.,White, David H.,Bertrand, William S.,Mokhtar, Rodziah,et al.
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p. 138 - 141
(2007/10/02)
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- Fluorodecarboxylation with Xenon Difluoride
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The reaction between xenon difluoride and aliphatic carboxylic acids causes decarboxylation with replacement of the carboxyl group by fluorine.
- Patrick, Timothy B.,Johri, Kamalesh K.,White, David H.
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p. 4158 - 4159
(2007/10/02)
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- Proton-Transfer Reactions. 2. Effects of Internal Return on Reactivity Difference between Alkoxide-Promoted Eliminations in tert-Butyl alcohol and Ethyl Alcohol
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Kinetics of alkoxide-promoted dehydrofluorination reactions are reported for the series C6H5CH2CH2F (I), C6H5CH2CHF2 (II), C6H5CH2CF3 (III), and C6H5CH2CF2CF3 (V).Rates and activation parameters 3 (M-1 s-1)(50 deg C), ΔH* (kcal mol-1), and ΔS*, (eu)> are respectively: (a) using potassium tert-butoxide in tert-butyl alcohol, I (1.88 * 10-4, 19.1, -16.8), II (1.18 * 10-3, 20.3, -9.3), III (2.15 * 10-3, 22.1, -2.4), V (3.93 * 10-2, 16.9, -12.7); and (b) using sodium ethoxide in ethanol, I (1.32 * 10-6, 25.6, -6.5), II (5.28 * 10-7, 29.7, 3.0), III (3.45 * 10-7, 32.6, 12.5), V (5.41 * 10-5, 27.7, 7.6).The variation in tert-butoxide:ethoxide ratios of 140 (I), 2200 (II), 6200 (III), and 730 (V) are discussed in terms of a two-step mechanism with varying amounts of internal return for II, III, and V.Differences in reactivity for groups attached to the benzylic carbon (-CF3, -CF2Cl, -CHF2, -CF2CF3) and variation of ΔS* values for these reactions are also discussed in terms of a two-step mechanism.
- Koch, H. F.,Tumas, W.,Knoll, R.
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p. 5423 - 5429
(2007/10/02)
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