Fluorous techniques for the synthesis and separation of organic molecules Dennis Curran and Zhiyong (Robert) Lee of the Chemistry Department at the University of Pittsburgh USA describe how fluorous techniques provide strategic new green options for conducting organic reactions and for separating the resulting reaction mixtures. The technology is especially suitable for the preparation of combinatorial libraries. The yield of every chemical step is limited both by the efficiency of the reaction and the ability to recover the pure product from the reaction mixture. However most traditional solution phase synthesis methods are concerned only with conversion of starting materials to products (reactions) and not with product separations. Fluorous techniques provide strategic new options for conducting solution phase organic reactions and for separating the resulting reaction mixtures.Fluorous molecules typically contain at least one highly fluorinated domain attached to an organic domain. The fluorinated domain can be an integral part of the molecule (permanent attachment) if the intended use is as a reagent reactant or catalyst. A temporary attachment of a removable fluorous group is required to render a reaction substrate or product fluorous. Fluorous compounds can be separated from standard organic compounds by simple workup techniques Dennis Curran Distinguished Service Professor and Bayer Professor of Chemistry at the University of Pittsburgh USA and Chairman of the Scientific Advisory Board of Fluorous Technologies Inc.of liquid–liquid extraction (two- or three-phase) or solid–liquid extraction. Fluorous compounds can also be separated from each other based on fluorine content by fluorous chromatography. Four different types of techniques are summarized fluorous biphasic catalysis fluorous reagents and reactants fluorous substrates (fluorous synthesis) and fluorous mixture synthesis. The techniques differ in the size and nature of the fluorous tag in the reaction conditions and in the separation method. Fluorous techniques are applicable to both green chemical process development and chemical discovery research. Many of these new techniques are especially suited to the preparation of combinatorial libraries by solution phase parallel synthesis.Organic Compounds a typical organic tin hydride • mediates diverse radical reactions but. • is difficult to separate from organic products Fluorous molecules Fluorous molecules are designed to mimic organic molecules in terms of reactivity yet to still be readily separable from other organic molecules. In the technique of fluorous mixture synthesis fluorous molecules are also separated from each other. Fluorous molecules typically have two domains. The organic domain resembles a standard organic parent molecule and dictates the reactivity of the molecule. The fluorous domain is a highly fluorinated group that controls the separation features of the molecule.Fluorous domains are often perfluoroalkyl groups. Shown below are two simple examples of fluorous molecules designed after common organic parents. Fluorous tin hydrides have similar reactivity to the classical reagent tributyltin hydride. But Fluorous Compounds a typical fluorous tin hydride • mimics the reactivity of its organic parent and. • is easy to separate from organic products by liquid-liquid extraction • recover and reuse are routine DOI 10.1039/b100266j This journal is © The Royal Society of Chemistry 2001 a typical Boc protected amide • easy to prepare by amide coupling but. • is difficult to separate from the coupling reagents F E A T U R E a fluorous Boc protected amide • prepared by the same methods as the standard Boc-amide and.• is easy to separate from the coupling reagents by solid-liquid extraction G3 Green Chemistry February 2001 F E A T U R E unlike tributyltin compounds the fluorous tin compounds are readily separable from organic compounds by simple fluorous separation techniques like liquid–liquid extraction or solid–liquid extraction. The fluorous domain of the tin hydride is permanently attached because there is never any need to separate it from the organic domain. The tin compounds are simply recovered at the end of the reaction and recycled. Although only one fluorous tin hydride is shown in the table on page G3 a whole family is now available whose members differ from each other by the length and number of the fluorinated chains and the length of the spacer.This allows the separation properties and (sometimes) the reactivity properties to be tuned for particular needs. The fluorous Boc group is a typical example of a fluorous protecting group that is designed to be attached and removed by analogy with the standard Boc group. Such fluorous protecting groups are also called ‘fluorous tags’ and they allow rapid separation of all tagged molecules from non-tagged molecules by fluorous solid phase extractions. A growing assortment of fluorous tags is now available. Fluorous separation methods Liquid–liquid extraction Perfluorinated or very highly fluorinated solvents are called ‘fluorous solvents’ and they are typically immiscible with organic solvents and water.They are used in liquid–liquid extractions to quickly separate fluorous compounds from organic compounds in a two-phase liquid–liquid extraction or from organic and inorganic (or water soluble organic) compounds in a three-phase liquid–liquid extraction. The most popular fluorous Green Chemistry February 2001 G4 This journal is © The Royal Society of Chemistry 2001 solvent is probably 3M’s FC-72™ but a number of related solvents are available and these are all comparably priced. A photograph of a typical three-phase liquid–liquid extraction is shown above. Such extractions are readily automated and can be used to quickly partition reaction mixtures into organic water-soluble and fluorous fractions.In many cases the crude organic products are pure enough to be taken on to the next reaction and the fluorous products can usually be recycled if desired. Liquid–liquid extractions work best when fluorous domains are relatively large. In the best cases only a single separation is needed. With lower partition coefficients the organic fraction is washed several times with the fluorous solvent. Thanks to the exceedingly low solubilities of organic compounds in fluorous solvents the washing process can be conducted repeatedly without extractive loss of the organic product. Liquid–liquid extractive methods are typically used when the desired product is organic and some other reaction component (reactant reagent catalyst scavenged product) is fluorous.Solid–liquid extraction Silica gel with a fluorocarbon-bond phase (‘fluorous reverse phase silica gel’) can be used to adsorb fluorous molecules and free them from non-absorbed organic molecules by the simple process of solid–liquid extraction illustrated below. Examples of fluorocarbon bonded phases include –Si(Me2)CH2CH2C6F13 –Si(Me2)CH2CH2C8F17 and –Si(Me2)(CH2)3C(CF3)2C3F7. In the separation stage a crude reaction mixture is charged to a suitable amount of fluorous silica gel and the silica is eluted first with a ‘fluorophobic’ solvent to remove the organic compounds while leaving the fluorous compounds adsorbed. In cases where the fluorous products are desired a second elution with a ‘fluorophilic’ solvent then provides this material.These fluorous solid phase extractions are different from traditional chromatographies and this is advantageous in a parallel setting. In solid phase extractions relatively high loadings of substrate/silica are used and all of the mixtures in the synthesis behave identically. No fractionation is needed. In traditional chromatographies each mixture behaves differently and lower loadings and carefully monitoring of fractions are needed. The solid–liquid extractions are operationally filtrations and they are easy to conduct in parallel either manually (see the manual solid-phase extraction apparatus below) or by using various automated techniques. In addition to the operational convenience solid–liquid extractions succeed with many fewer fluorines in the fluorous domain compared to liquid–liquid extractions.For this reason solid–liquid extractions are especially useful when the desired product of the reaction bears a fluorous tag. The solid phase extraction is applicable in essentially all areas from traditional synthesis through parallel synthesis and is especially useful for parallel synthesis of intermediates. Solid–liquid extraction is currently the most general and most easily implemented fluorous–organic phase separation technique. It is useful for the gamut of fluorous methods. Fluorous solvents are rarely needed for the extractions and they are used only to wash the silica prior to reuse if desired.Fluorous chromatography The separation of fluorous molecules from each other can sometimes be accomplished by standard chromatographic techniques including traditional or reverse phase chromatography. However the best way to separate fluorous compounds from each other is usually by chromatography over fluorous silica. These separations capitalize on the unique feature of fluorous solid phases which is their ability to separate molecules primarily by fluorine content. An illustrative example of this is shown below with a family of fluoroacyl-tagged amides. The control compound lacking the fluorous tag (C7H15) comes off with the solvent front as do most other non-fluorinated organic compounds under these conditions.The fluorinated homologs then emerge strictly in order of fluorine content and a solvent gradient is needed to push the more highly fluorinated members of the series off the column. Many popular fluorous techniques involve fluorous–organic separations so preparative fluorous chromatography is not needed. However fluorous chromatography still has two major uses. First it can be used in methods development experiments to select suitable solvents for fluorous–organic solid phase extractions thereby ensuring in advance that separation conditions are suitable. Second it can be used to analyze the purity of essentially any kind of fluorous component and it provides information that is largely complementary to traditional chromatographic analyses.In contrast to other methods fluorous mixture synthesis techniques rely heavily on fluorous chromatography for the separation of tagged compounds by the fluorine content of the tag. Fluorous biphasic catalysis What we now call ‘Fluorous Biphasic Catalysis’ (FBC) was first introduced in the thesis of Dr. M. Vogt in Aachen in 1991. This work was known to almost no one and a seminal paper by Horváth and Rábai in 1994 introduced new concepts and results along with today’s terminology. Since that time fluorous biphasic catalytic methods have advanced rapidly and a large number of fluorous catalysts and ligands (especially phosphines) are known. The defining feature of FBC is the use of a fluorous reaction solvent and the technique is best viewed as a liquid phase catalyst immobilization method.Hydroformylation with a fluorous variant of Wilkinson’s catalyst provides a typical example of fluorous biphasic catalysis below. A toluene solution of an F E A T U R E enone and a silane is heated with a perfluoromethylcyclohexane solution of the catalyst. After the reaction is complete the mixture is cooled and the two phases are separated to provide the organic hydrosilylation products and the recovered catalyst immobilized in the fluorous phase. In an important variant of fluorous biphasic catalysis an organic solvent is choosen such that on warming a homogeneous (one phase) solution results. After the reaction is complete the mixture is cooled to induce the phases to separate once again.In the hydrosilylation example the replacement of toluene by hexane allows for one phase reaction and two phase separation. FBC and related methods are ideally suited for economical and green chemical processes. A single liquid–liquid separation provides both the product and the recovered catalyst. The safety of fluorous solvents is also an attractive feature. For the single separation to succeed high partition coefficients are needed so the catalysts generally have large numbers of fluorines. Fluorous catalysts have advantages over solid-supported catalysts since they can be soluble in the reaction medium. Water-based biphasic catalysis reactions are also used but are obviously limited to water-tolerant processes.Fluorous catalysts do not share this limitation. Fluorous reagents reactants catalysts For many types of organic reactions it is desirable to use fluorous reaction components (reagents reactants catalysts) with fewer fluorines. Such molecules have advantages of lower molecular weight and increased solubility in organic solvents. With these types of molecules fluorous reaction solvents are not used and the fluorous phase (either solid or liquid) is used only in the separation stage. The reductive radical cyclizations with the family of fluorous tin hydrides shown below illustrate many of the features of this branch of fluorous chemistry. In general the substrate and the product are organic molecules and one of the other reaction components (in this case the tin hydride) is fluorous.The fluorous component can be used either catalytically or stoichiometrically and the reaction and separation stages are decoupled. After standard reactions members of the tin hydride family with more fluorines can be separated either by liquid–liquid extraction or by solid–liquid extraction while the solid–liquid Green Chemistry February 2001 G5 This journal is © The Royal Society of Chemistry 2001 F E A T U R E (C6F13CH2CH2)3SnH yes (3) (C4F9CH2CH2)3SnH yes (8–10) (C6F13CH2CH2CH2)3SnH yes (5–8) (C4F9CH2CH2CH2)3SnH yes (10–12) C10F21CH2CH2SnMe2H yes (3) C extraction is preferred for members with fewer fluorines.For the most highly fluorinated member of the series a fluorinated reaction co-solvent like benzotrifluoride (C6H5CF3) is needed. Benzotrifluoride is not a ‘fluorous’ solvent since it is miscible in all organic solvents (and indeed dissolves many types of organic compounds as well) but it still aids in the solubilization of fluorous compounds in the reaction medium. These types of methods are broadly useful for all types of organic synthesis from process chemistry (fluorous catalysts preferred) through traditional synthesis to solution phase parallel synthesis and combinatorial chemistry. Tuning of preferred reaction solvents and separation methods is accomplished by selecting a reagent with an appropriate fluorine content.The reagents with fewer fluorines are especially attractive since they often have excellent solubility in organic solvents yet can still be separated from standard organic compounds by solid–liquid extraction. Fluorous compounds are also soluble in supercritical CO2 and can be used in green chemical reactions in that solvent. The general solubility of the fluorous reaction components is an attractive feature in comparison to reagents quenchers and catalysts that are immobilized on insoluble polymers. The term ‘fluorous synthesis’ is often used to describe techniques in which the substrates and/or desired products are rendered fluorous. This technique is a phase tagging strategy that is conceptually analogous to ‘solid phase synthesis’ but with major operational Green Chemistry February 2001 differences.Making substrates and products fluorous necessarily involves cleavable tags (since the final product will not be tagged) and fluorous protecting groups or traceless tags can be used. Fluorous synthesis concepts were introduced with liquid–liquid separation methods coupled with very large fluorous tags (60–120 fluorines). These early ‘heavy’ fluorous techniques are quickly being replaced by ‘light’ techniques where tags with many fewer fluorines are used coupled with solid–liquid extraction. Amino acids are readily coupled to make amides by first tagging the amine with a fluorous acyl group or a fluorous Boc group and then coupling the acids with amines under standard conditions (below).In general only about 15–19 fluorines are needed and the resulting tagged molecules have solubility properties that are largely dominated by the organic domain. In other words they are soluble in organic not fluorous solvents. However the solid phase extraction (SPE) properties of the molecule are still dominated by the fluorous domain. The protected acids are coupled with amines under standard G6 tin hydride I-I extraction s-l fluorinated (no. of extractions) extraction rxn cosolvent? yes yes no yes no yes no yes no yes no yes no 8F17CH2CH2SnMe2H Summary Fluorous substrates products This journal is © The Royal Society of Chemistry 2001 conditions. The desired tagged products are then retained on the column in the first pass of the solid phase extraction (MeOH/water) while all the coupling reagents reactants and byproducts are eluted off.The coupled fluorous products are then eluted off in a second pass (MeCN) and are obtained in excellent purity. Fluorous synthesis is attractive because a single protecting group or tag can be used to render a library of organic molecules fluorous. The resulting library of soluble molecules can then be separated from broad classes of organic and inorganic reagents reactants side products etc. by solid phase extraction. Unlike polymer-bound molecules the fluorous-tagged compounds are small molecules that can be analyzed and characterized by standard small molecule techniques.The tagging methods are ideal for expedited parallel synthesis and for the gram-scale preparation of chemical intermediates in parallel. Because the tagged compounds have relatively few fluorines they can be reacted under typical conditions for non-tagged molecules and the solid phase extraction gives a fast yet substantive separation. In the final detagging step solid phase extraction can again be used to separate the organic product from the remnant of the fluorous tag. The tag can often be recovered in a form suitable for reuse if desired. In addition to fluorous acyl and Boc groups there are now a number of fluorous silyl groups fluorous THP groups fluorous benzyl groups etc. By directly addressing the separation problems inherent in the synthesis of small organic molecules fluorous techniques provide an array of powerful solutions that span the discipline of organic synthesis from large-scale chemical processes through traditional Fluorine Content Rxn Solvent Technique fluorous and organic Fluorous biphasic high catalysis low-medium Fluorous reagents organic or hybrid liquid–liquid or solid–liquid extraction organic low Fluorous substrates organic low variable Fluorous mixture synthesis fine synthesis to modern chemical discovery by combinatorial methods.The above Table summaries the four main fluorous methods outlined in this overview and compares and contrasts them. Fluorous methods are attractive and easy to apply because the experimental techniques (solution phase reactions liquid–liquid extractions solid phase extractions) are familiar to practicing organic chemists.What differs from standard organic techniques are the fluorous components that are used. The application of fluorous techniques has been limited to a few specialized laboratories due to the lack of availability of fluorous reagents reactants tags solvents silica etc. However a new company Fluorous Technologies (see box) intends to change this by providing laboratories worldwide with both the materials and the expertise that are needed to integrate fluorous methods into their ongoing discovery and production projects. Fluorous Technologies Inc.Fluorous Technologies Inc is a newly formed company based in Pittsburgh PA. It has licensed from the University of Pittsburgh several patents and pending patent applications for the use of fluorous organic chemistry for chemical synthesis isolation and purification. Investors in the company include Albany Molecular Research Inc Alfred Bader and retired founder of Aldrich Chemical Company and the University of Pittsburgh. Denis Curran is chairman of the Scientific Advisory Board for the company. See http://www. fluorous.com for further information. Uses Separation green chemical processes single liquid– liquid separation universal solid–liquid extraction chemical discovery intermediate synthesis fluorous chromatography leveraged chemical discovery Selected references Reviews D.P. Curran Combinatorial Organic Synthesis and Phase Separation Back to the Future Chemtracts—Org. Chem. 1996 9 75–87 D. P. Curran Strategy-level separations in organic synthesis From planning to practice Angew. Chem. Int. Ed. Engl. 1998 37 1175–1196. J. J. Maul P. J. Ostrowski G. A. Ublacker B. Linclau and D. P. Curran Benzotrifluoride and Related Solvents in Organic Synthesis In Topic in Current Chemistry Modern Solvents in Organic Synthesis; P. Knochel Ed.; Springer-Verlag Berlin 1999 206 80–104. D. P. Curran Parallel Synthesis with Fluorous Reagents and Reactants Med. Res. Rev. 1999 19 432–438. D. P. Curran S. Hadida A. Studer M.He S.-Y. Kim Z. Luo M. Larhed M. Hallberg and B. Linclau Fluorous Synthesis A User s Guide In Combinatorial Chemistry A Practical Approach (H. Fenniri Ed.) Oxford Univ. Press Oxford Vol. 2. in press. D. P. Curran Fluorous Techniques for the Synthesis of Organic Molecules A Unified Strategy for Reaction and Separation in Stimulating Concepts in Chemistry Wiley-VCH in press. Fluorous Biphasic Catalysis I. T. Horvath J. Rabai Facile catalyst separation without water Fluorous biphase hydroformylation of olefins Science 266 72–75. F E A T U R E I. T. Horvath Fluorous biphase chemistry Acc. Chem. Res. 1998 31 641–650. Y. Nakamura S. Takeuchi Y. Ohgo D. P. Curran Asymmetric alkylation of aromatic aldehydes with diethylzinc catalyzed by a fluorous BINOL-Ti complex in an organic and fluorous biphase system Tetrahedron Lett. 2000 41 57–60. Fluorous Reagents D. P. Curran S. Hadida Tris(2-(perfluorohexyl)ethyl)tin hydride A new fluorous reagent for use in traditional organic synthesis and liquid phase combinatorial synthesis J. Am. Chem. Soc. 1996 118 2531–2532. D. P. Curran S. Hadida S. Y. Kim Z. Y. Luo Fluorous tin hydrides A new family of reagents for use and reuse in radical reactions J. Am. Chem. Soc. 1999 121 6607–6615. Fluorous Synthesis A. Studer S. Hadida R. Ferritto S. Y. Kim P. Jeger P. Wipf D. P. Curran Fluorous synthesis A fluorous-phase strategy for improving separation efficiency in organic synthesis Science 1997 275 823–826. D. P. Curran Z. Y. Luo Fluorous synthesis with fewer fluorines (Light fluorous synthesis) separation of tagged from untagged products by solid-phase extraction with fluorous reverse-phase silica gel J. Am. Chem. Soc. 1999 121 9069–9072. Fluorous Mixture Synthesis Y Oderaotoshi Q. Zhang Z. Luo and D. P. Curran Fluorous Mixture Synthesis The First Strategy for the Synthesis of Mixtures of Organic Compounds that Provides Pure Individual Products through Demixing Controlled by the Fluorous Tag in preparation. Green Chemistry February 2001 G7 This journal is © The Royal Society of Chemistry 2001