Green Chemistry Fluorous Ethers Journal: Green Chemistry Manuscript ID: GC-CRV-06-2015-001345.R3 Article Type: Critical Review Date Submitted by the Author: 11-Aug-2015 Complete List of Authors: Lo, Angel; City University of Hong Kong, Department of Biology and Chemistry Horvath, Istvan; City University of Hong Kong, Department of Biology and Chemistry Page 1 of 12 PleaseGreen do not Chemistry adjust margins Green Chemistry Review Fluorous Ethers Angel S. W. Lo and István. T. Horváth Received 00th January 20xx, Accepted 00th January 20xx Fluorous ethers having one or more fluorous ponytails containing longer and shorter F(C xF2x )-perfluoroalkyl substituent(s) where (x ≥ 6) or (x = 1 - 5), respectively, were reviewed including some of their basic properties, synthesis and selected DOI: 10.1039/x0xx00000x applications in chemical processes. www.rsc.org/ The most popular green solvents are water, alcohols, ionic Introduction liquids, and supercritical fluids. 5 Although many of them exhibit very attractive solvent properties and have been used Solvents have been playing an important role to perform successfully, they are not necessarily free of environmental chemical reactions and processes, isolate and purify chemical and/or health issues. The polar green solvents such as water, compounds by extraction, crystallization, or azeotrope alcohols, and some of the ionic liquids could distribute low distillation, clean surfaces, and assist the structural and 1 level polar contaminations including toxic chemicals. Ionic analytical characterization of chemicals. Traditionally, the liquids have become very popular, 11 though their toxicity could right combination of physical and chemical properties of be an issue, especially if their solubility in water could lead to molecules were the only important criteria to select suitable contamination. Supercritical carbon dioxide and water have solvents or design new ones. Well-known and publicized 12 2 emerged as green solvents, though the required higher solvents related accidents as well as the negative pressures increase the risks for accidents. In all cases, the environmental and health effects of some of the commonly 3 4 environmental benefits offered by the greener solvents must used solvents have changed the selection strategies and be a contributor to their favourable economic performance. requirements: low vapour pressure, no or low flammability, no While a broad range of greener polar solvents are available, or low toxicity, low persistency, and high biodegradability have 5 only a few non-polar solvents have been developed. The most become additional features of todays preferred solvents. For non-polar chemicals are the perfluorinated alkanes (C F ), example, chlorofluorocarbons (CFCs) were developed as a x 2x+2 dialkylethers ([C xF2x+1 ]2O), and trialkyl amines ([C xF2x+1 ]3N), safe, non-toxic, and non-flammable replacement of toxic and 13 6 which could be used as solvents as well. dangerous refrigerants, such as ammonia and sulfur dioxide. In addition, they were widely used as cleaning solvents, Fluorous Biphasic System (FBS) agricultural propellants, and blowing agents. Their increasing Perfluorinated liquid compounds could easily form liquid-liquid popularity led to more and more releases to the atmosphere, 7a biphasic systems with polar organics. The facile separation of which resulted in the ozone depletion. The production of the perfluorinated liquid reach phase was the basis of the CFCs ceased globally by the middle of the nineties and the 7b fluorous biphasic concept, which was introduced together with ozone layer is on track to recovery. Hydrofluoroethers (HFEs) the term fluorous, in 1994. 14 Fluorous transformations should are emerging alternatives to replace perfluorocarbons (PFCs), 8 be controlled by carefully designed fluorous reagents or CFCs, and hydrochloro-fluorocarbons (HCFCs). HFEs have catalysts, which are preferentially soluble in the fluorous phase shorter life-time in the atmosphere due to their facile 9 and has limited solubility in the product phase (Scheme 1). decomposition by their reaction with hydroxy radicals. Consequently, HFEs have no ozone depletion and low global warming potentials. Since HFEs are less expensive and considerably less persistent and toxic in the environment, they have been used as refrigerants, cleaning solvents, blowing and degreasing agents. 10 Scheme 1 Fluorous biphasic system This journal is © The Royal Society of Chemistry 20xx J. Name ., 2013, 00 , 1-3 | 1 Please do not adjust margins PleaseGreen do not Chemistry adjust margins Page 2 of 12 ARTICLE Journal Name The temperature regulation of the fluorous biphasic systems 4. CF 3(CF 2)m-CH 2-X where X is any chemical moiety; leading to one phase at higher temperatures and two phases 5. CF 3(CF 2)m-Y-X where Y = non-S, non-N heteroatom and at lower temperatures, a simple approach to control mass where X is any chemical moiety. transfers via thermoregulation, was also recognized. 14 The bioaccumulation and toxicity of the homologues of The introduction of the fluorous biphasic concept was perfluoroalkyl caboxylates is higher for longer compared to followed by the rapid development of fluorous chemistry, 15 those with shorter perfluoroalkyl chain lengths. 20 Therefore, 16 which is closely connected to organofluorine chemistry. the combination of shorter C 1-4-perfluoroalkyl-groups was While the latter is dedicated to the fundamental aspects of suggested to maintain high fluorous solubility and partition making and breaking carbon-fluorine bond(s), fluorous and minimize bioaccumulation. 22 chemistry is concerned with the design and attachment of perfluoro-alkyl group(s) containing substituents to the hydrocarbon domains of fluorous reagents and catalysts to Synthesis of C6-10 Perfluorinated Alkyl group(s) ensure their efficient solubility and separation (Scheme 1). Containing Fluorous Ethers Originally, 14 high fluorous partition ( P = c /c F fluorous phase other phase Examples of available long-chain perfluorinated alkyl in 50/50 vol.% c-C F CF /toluene) 17 or fluorophilicity (ln P )18 6 11 3 F ethers are listed in Table 1. Fluorination of dialkyl-ethers and - of the fluorous compounds was achieved by the attachment of polyethers has been the most used direct synthesis of C -C -perfluoroalkyl ponytails to the hydrocarbon domains of 6 12 perfluoroethers such as 1, 4 and 13 with different molecular fluorous reagents or catalysts in appropriate number. weights and boiling points (Table 1).23 Commercially attractive fluorous systems should be Fluorous ethers 2a-d, 9a-c and 12 (Table 1) have been designed to remain inside the laboratory or the production prepared by reacting fluorous alcohols with alkyl bromides in facility. However, low level leaching of a fluorous reagent or a the presence of KOH in N-methyl-2-pyrrolidone (Scheme 3). 24 catalyst to the product(s) or its accidental releases could result in long term environmental and health issues. If a fluorous compound with a long perfluoroalkyl group would enter the environment, its oxidative and/or hydrolytic fragmentation would lead to the formation of a long-chain perfluoroalkyl Scheme 3 Synthesis of fluorous ethers involving nucleophillic substitution. caboxylate (LCPFAC) (Scheme 2), among which perfluoro- 19 ocatanoic acid (CF 3(CF 2)6-COOH or PFOA) is the best known. Long-chain containing fluorous ethers 3 and 8 (Table 1) were synthesised by preparing fluorous iodides from fluorous allyl ethers and perfluoalkyl iodides in the presence of AIBN and aqueous Na 2S2O5, followed by the heterogeneous 25 Scheme 2 Proposed formation of perfluoalkyl caboxylate from fragmentation of long- palladium catalysed hydrogenation (Scheme 4). chain fluorous compound in environment. PFOAs and some of their precursors are persistent, widely present in humans and the environment, have long half-lives in humans, can cause adverse effects in laboratory animals, and were linked to developmental and reproductive problems, liver toxicity and cancer. 20 Under the Toxic Substances Control Act, US Environmental Protection Agency (EPA) has recently Scheme 4 Formation of fluorous ether by radical reaction of fluorous vinyl compound 21 proposed to amend a significant new use rule for LCPFACs, and fluorous iodide. where 5 < n < 21 or 6 < m < 21: 1. CF 3(CF 2)n-COO-M where M = H + or any other group where A series of fluorous dialky-ethers 5 – 7, 10 and 16 (Table 1) a formal dissociation can be made; were prepared by using the Mitsunobu reaction of perfluoro 26 2. CF 3(CF 2)n-CH=CH 2; and perfluoroalkyl alcohols (Scheme 5). 3. CF 3(CF 2)n-C(=O)-X where X is any chemical moiety; Scheme 5 Mitsunonu reaction of perfluoro- and fluorous alcohols 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 12 PleaseGreen do not Chemistry adjust margins Green Chemistry Review Table 1 – C6-10 Perfluorinated alkyl group(s) containing fluorous ethers MW F Yield Compound Formula mp [°C] bp [°C] Ref [g/mol] [w%] [%] C7F16 O 404 75.2 N/A 36 N/A 23 R = C 2H5 (2a ) C10 H9F13 O 392 63.0 < -80 65 97 R = C 3H7 (2b ) C11 H11 F13 O 406 60.8 < -80 145 71 24 a R = C 5H11 (2c ) C13 H15 F13 O 434 56.9 - 46.8 110 72 b R = C 8H17 (2d ) C16 H21 F13 O 476 51.9 - 21.2 150 71 C15 H8F24 O 660 69.1 N/A 210 82 25 C12 F26 O 654 75.5 N/A 179 N/A 23 195- C H F O 596 70.1 ca. -70 71 26 13 6 22 199 180- C H F O 904 67.3 -10 to -8 66 26 21 12 32 2 190 c 170- C H F O 1054 68.5 24 - 26 85 26 24 12 38 2 180 c 88 25 C25 H14 F38 O2 1068 67.6 Oil, N/A >260 R = C 2H5 (9a ) C12 H9F17 O 492 65.7 < - 80 72 97 24 R = C 3H7 (9b ) C13 H11 F17 O 506 63.8 < - 80 165 82 24 b R = C 5H11 (9c ) C15 H15 F17 O 534 60.5 - 19.4 130 82 24 224- C H F O 696 71 - 37 91 26 15 6 26 227 Liquid, C H F O 448 13.7 214 92 27 14 17 13 N/A This journal is © The Royal Society of Chemistry 20xx J.