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Modern fluoroorganic chemistry : synthesis, reactivity, applications

Vinter, J. Perkin Trans. Lorenzo, G. Lewis, I. Dance, New J. Dahl, Acta Chem. Williams, Acc. Kirsch, M. Bremer, Angew.

Rowland, Angew. Rowland, Nature , , — Ko, N. Sze, J. Rodriguez, D. Weisenstein, C. Heisey, R. Wayne, P. Biggs, C. Canosa-Mas, H. Sidebottom, J. Treacy, Geophys. McCulloch, J. Sturges, T. Wallington, M. Hurley, K. Shine, K. Shira, A. Engel, D. Oram, S. Penkett, R. Mulvaney, C. Brenninkmeijer, Science , , — Environmental Protection Agency. Gerstell, J. Francisco, Y. Yung, C.

Boxe, E. Aaltonee, Proc. Acad Sci. Baasner, H. Hagemann, J. E 10a, Georg Thieme, Stuttgart, , pp. Marais, Onderstepoort J. Stryer, Biochemistry, 3rd edn. Freeman, New York, , pp. Peters, Adv. Hogue, Chem. News April 21 , 9. Berger, S. Braun, H. All these experiments, either at room temperature or at liquid nitrogen temperature, resulted in sometimes violent explosions.

No major defined reaction products could be isolated. A plausible, first explanation for these discouraging results was proposed by W. To control the immense reaction enthalpy the fluorine gas was diluted with nitrogen or carbon dioxide. A similar line of work was pursued in the United States by L. Bigelow [4] who studied the reaction of arenes with fluorine gas. In an alternative approach, volatile organic substrates were fluorinated in the gas phase on contact with a copper mesh. This work was pioneered by Fredenhagen and Cadenbach in the early s [5] and then continued by Bigelow and Fukuhara [6] as a part of the Manhattan Project Figure 2.

Vapor phase fluorination finally enabled the preparation of relatively defined polyfluorination products from aliphatic hydrocarbons, benzene, or acetone. A modern, improved version of this general method, the LaMar Lagow—Margrave process, uses a nickel reactor with different temperature zones and silverModern Fluoroorganic Chemistry. At the top the proposed mechanism of free radical direct fluorination of alkanes is shown [8]. Scheme 2. During the reaction, the concentration of fluorine in proportion to inert gas is slowly increased [7].

Another method used to control the high reaction enthalpy of fluorination is coating of the organic substrate as a thin film on sodium fluoride powder and reaction in a moving bed reactor with fluorine gas, diluted with nitrogen or helium. Slow, stepwise increase of the fluorine concentration also enables clean perfluorination of rather complex substrates [9] Scheme 2.

The first pure and fully characterized perfluorocarbons PFC were obtained by the reaction of graphite with fluorine gas, yielding mainly carbon tetrafluoride [10]. The industrial scale procedure probably most important for synthesis of perfluorocarbon-based solvents was developed during the Manhattan Project [12] Figure 2. In the second step, the organic Figure 2. The CoF2 formed is regenerated i. The cobalt trifluoride process is of particular value for industrial perfluorination of organic substrates and it is based on the findings by Ruff and coworkers in the s that high-valence metal fluorides such as AgF2, CoF3, or MnF3, are highly effective oxidative fluorination agents.

Typical product distributions and the nature of the various rearrangement products indicate that the mechanism of the CoF3 and related processes involves single-electron transfers and carbocationic intermediates [14] Scheme 2. The mechanism is assumed to involve single electron transfers and carbocationic intermediates [8]. Although the cobalt trifluoride process is most suitable for the production of industrial-scale quantities of perfluorocarbons, other high-valence metal fluorides also are attractive additions to the methodology toolbox for selective fluorination on a laboratory scale.

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K2PtF6 was recently used for the selective fluorination of buckminsterfullerene C60 to the partially fluorinated fluorofullerene C60F18 which was not accessible by other methods [15] Figure 2. A major disadvantage of such metal fluorides, with extremely strong oxidizing power, in routine application is, nevertheless, the need to work either with volatile substrates in the gas phase or to use either no solvent at all or anhydrous hydrofluoric acid as the only stable reaction medium. Figure 2. The reaction enthalpy is controlled by dilution of the substrate in this solvent, by dilution of the fluorine gas with nitrogen or helium, and by use of a low reaction temperature.

Under these conditions, the selective fluorination of cyclohexane derivatives in the tertiary axial position is possible in reasonable yields [16] Scheme 2. Under similar conditions selective addition of fluorine to double bonds, even with complex organic substrates such as steroids, can also be achieved [17] Scheme 2. One of the first examples of industrial application of selective direct fluorination was the synthesis of the cytostatic 5-fluorouracil. In the most commonly used process the precursor uracil is treated with nitrogen-diluted fluorine in hot water and the intermediate fluorohydrin is subsequently dehydrated either by heating the aqueous solution to hC or with sulfuric acid [18] Scheme 2.

During the last few years, especially, there have been great advances in the selective direct fluorination of even sensitive organic substrates. Some of the methods introduced by R. The selective fluorination of b-dicarbonyl derivatives is best achieved in acetonitrile which, because of its stability, is a particularly suitable solvent for direct fluorination. Typical reaction temperatures are conveniently in the range 0 to 5 hC.

With dialkyl malonates addition of catalytic amounts of copper II nitrate enables selective formation of the mono-fluoromalonates almost without difluorinated byproducts [19] Scheme 2. Enol acetates are cleanly converted into the respective a-fluoroketones [20]. Copper salt catalysis supposedly acts via formation of the copper enolate complex [19, 20]. The formation of the corresponding copper complex of monofluoromalonate, the precursor of difluorinated products, is energetically disfavored. Arenes are best fluorinated in acidic solvents such as sulfuric acid or formic acid, to obtain an electrophilic mechanism Scheme 2.

The main obstacle to large-scale industrial application of the potentially inexpensive direct fluorination of aromatic compounds is the difficult separation of the regioisomers and other by-products with higher or lower fluorine content. A more recent approach to the control of the large reaction enthalpies in technical-scale direct fluorination is the use of microreactors [22]. These have three advantages compared with conventional arrangements: 1 the high surface-tovolume ratio for contact between gas and liquid phase is especially advantageous for direct fluorinations, because it enables good mixing of the reactants and good temperature control; 2 because the actual reaction volume is very small, the risk of runaway reactions or explosions is significantly reduced; and 3 the upscale to industrial throughput is conveniently accomplished by the parallel operation of as many microreactors as necessary.

Ab-initio calculations indicate that even for the complex of F2 with the extremely strong hydrogen-bond donor HF as a model system, the energy of complex formation is very low — only 0. Because of the low polarizabilScheme 2. The formation of the complex is slightly exothermic by 0. Rozen [16] and R. Chambers [21a]. Theoretically there are clear indications that the proposed electrophilic mechanism involving significant polarization of F2 either by a C—H bond of the substrate or by a hydrogen bridge-donating solvent has to reconsidered.

This process was pioneered by J. Simons and coworkers in but published only after declassification in [26].

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For electrochemical fluorination, the organic substrate is dissolved in anhydrous hydrofluoric acid aHF at 0 hC and a current is passed through the solution at a potential of 4. Sometimes additives are used to increase the conductivity. In this voltage range, at the nickel anode, where the fluorination occurs, no fluorine gas is evolved, but hydrogen is evolved at the steel cathode, which is usually also the reaction vessel.

With increasing fluorination the solubility of the products in aHF decreases and, finally, the perfluorinated products formed at the anode become immiscible with aHF and form a separate phase which is more dense than the solvent. They can, therefore, be easily removed from the bottom of the reaction vessel. ECF provided, for the first time, at reasonable cost, commercial quantities of the technically important trifluoroacetic acid and trifluoromethyl and perfluorooctyl sulfonic acids Scheme 2.

The organic substrate is oxidatively fluorinated by high-valence nickel fluorides at the anode surface [28]. It currently provides the precursors to the palette of more than large-scale fluorine-containing compounds produced by this company [27]. These products include fluorotensides, fire-fighting chemicals, perfluorinated solvents, and artificial blood substitutes. Electrochemical formation of high-valence nickel fluorides with strong fluorinating power at the nickel anode has been discussed as the key to the mechanism of ECF [28] Figure 2.

This hypothesis is supported by the findings of N. Bartlett and coworkers that chemically generated NiF3 and NiF4 in aHF are also very effective perfluorinating reagents [29]. In aliphatic nucleophilic substitution SN reactions, fluoride as the leaving group is the most inert halogen order of nucleofugicity I i Br i Cl i F , because of the very strong carbon—fluorine bond and the high charge density of the liberated fluoride ion.

The behavior of the fluoride ion as a nucleophilic species is, however, bizarre — depending on the reaction environment it can act either as an extremely poor nucleophile in a protic solvent or as a very powerful nucleophile in polar aprotic solvents, especially with large lipophilic cations. An alkyl iodide, bromide, or tosylate is heated in a polar solvent with an alkali fluoride and the volatile alkyl fluoride is removed by distillation during the reaction [30] Scheme 2. For safe handling of primary alkyl fluorides it must be kept in mind that the even-membered compounds of this series are toxic, because they can be oxidatively metabolized to the poisonous fluoroacetate [31].

The volatile alkyl fluoride is removed from the reaction mixture by distillation [30]. To avoid this problem, crown ethers or phase-transfer catalysts with large, lipophilic cations are often used to render nucleophilic fluorinations more efficient. Because of the unique position of fluorine in the periodic system, it is the smallest possible mono-anion with the largest negative charge density. The fluoride ion therefore acts as an extremely strong hydrogen-bond acceptor. This and its low polarizability are the reasons for the relatively moderate nucleophilicity in protic solvents.

In contrast, in polar aprotic environments where no potential hydrogen bond donors are available and no close interaction with the cation occurs, fluoride acts as a very potent nucleophile and as a strong base. Suitable systems are, e. Many crystal structures of fluorides with organic counter-ions show the fluoride ion in close, hydrogen-bonding-like contact with, e. Preparatively, it is sometimes not possible to remove traces of hydrogen-bonded water or alcohols from the fluorides without decomposing the organic cation.

Under such conditions the fluoride is generated in the last step of the synthesis by thermolyzing the corresponding tetrafluoroborates e. Another stabilization strategy is to use kinetically labile difluorotrimethylsiliconates e. Me2NH, PhCl; r. In contrast with alkali fluorides, even the moderately active tetrabutylammonium fluoride TBAF in THF is an effective reagent for nucleophilic ring opening of epoxides Scheme 2. Lewis Acid-assisted Fluorination There are two principal ways of increasing the reactivity of the fluoride ion as a nucleophile.

The use of Lewis catalysts increases the reaction rate of nucleophilic exchange dramatically. The thermodynamic direction of the reaction is again determined by the strong carbon—fluorine bond. The pioneering work in this field was performed by F. Swarts starting from Stoichiometric amounts of the Lewis catalysts themselves can also serve as the fluoride source [41]. The catalytic halogen exchange works especially well in the benzylic position of aromatic compounds, giving access to a variety of industrially important fluorinated solvents [42, 43] and intermediates [44] Scheme 2.

Typically, these substances were synthesized with anhydrous hydrofluoric acid as the source of fluoride and catalytic amounts of SbCl5 at temperatures below hC. The nomenclature of CFC is discussed in Section 4. A newer field of application of Swarts fluorination in carbohydrate chemistry is the synthesis of glycosyl fluorides from the corresponding bromides [46] Scheme 2. The trifluoromethylzinc bromide bis acetonitrile complex acts as the fluoride source and electrophilic catalyst at the same time [46].

In glycosylation reactions they serve as the glycosyl donor.

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications - PDF Free Download

The glycosyl acceptor subsequently adds to the resulting resonance-stabilized carbocation intermediate. Not only hydrofluoric acid can be used as the fluoride source, but also other fluoroaliphatic compounds, for example fluoromethyl ethers [54] Scheme 2. Most preferred reaction products are trifluoromethyl derivatives, followed by geminal difluoromethyl derivatives.

For example, in the top example the formation of CF3CCl3 is energetically preferred by ca 5. Amine—Hydrogen Fluoride and Ether—Hydrogen Fluoride Reagents Hydrofluoric acid itself is one of the most hazardous reagents used in fluorine chemistry, possibly more so than elemental fluorine itself. Reasons are the low boiling point of aHF Like anhydrous HF, pyridine—HF etches glass and is highly toxic but, because of its lower vapor pressure, handling is much safer. It was soon found that by changing the ratio of amine to HF the acidity and nucleophilicity of this and similar reagents could be modified in a wide range.

A further improvement of safety and ease of handling was the use of polyvinylpyridine as a solid base [56]. Of course, the general concept works not only with pyridine as a hydrogen bridge acceptor. Triethylamine tris hydrogen fluoride b. As a result of these developments, in preparative fluoroorganic chemistry there usually is no longer any need to use anhydrous hydrofluoric acid.

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For halofluorination of multiple bonds there is no need for a strongly acidic fluorination reagent. Selection of suitable amine—HF reagents therefore becomes broader than for hydrofluorination. There is also a wide choice of electrophiles for initiating the reaction. The trans stereochemistry of the halofluorination product indicates the formation of a three-ring, bridged intermediate which is subsequently opened by attack of a fluoride ion [63]. Occasionally the 1-fluorohaloalkane formed initially is converted in situ into the corresponding 1,2-difluoroalkane by further reaction with silver fluoride.

If the group X is bromine or iodine it can be replaced by fluorine in situ with AgF [63—65]. The phenylselenyl moiety can be removed later, either by using m-chloroperbenzoic acid MCPBA to give fluoroalkenes or by radical reduction to furnish the fluoroalkane Scheme 2. AgF; r. Opening of epoxides to give b-fluoroalcohols can also be achieved by use of amine—HF reagents. Because of the very different acidity and nucleophilicity of the various reagents, the stereoselectivity of the reaction can be modulated [67].

With neutral to basic reagents the ring opening proceeds via nucleophilic attack of a hydrofluoride ion on the more electropositive carbon of the epoxide ring SN2-like [68]. If an acidic complex is used the primary step is protonation of the oxygen, followed by nucleophilic ring opening SN1-like [69] Scheme 2. With a chiral salen catalyst even enantioselective synthesis of chiral fluorohydrins can be achieved [70]. This type of reaction is of enormous interest for enantioselective synthesis of fluoropharmaceutical compounds Scheme 2. Defluorination can be accomplished by contact with hot hC iron or iron oxide.

After reducing the perfluoroaliphatic compound the metal surface can be regenerated by passage of hydrogen gas. This method has been scaled up to a continuous flow process for industrial synthesis of a variety of perfluorinated aromatic compounds Scheme 2. Others are complex catalytic systems which achieve the defluorination even at room temperature [8, 76] Scheme 2. Mg-anthracene, THF; r. An isolated arene diazonium tetrafluoroborate is thermolyzed at up to hC to yield the corresponding fluoroaromatic compound. Because of the infamously hazardous nature of isolated diazonium salts the scope of the classical variant of the Balz—Schiemann reaction was limited to the small scale.

The high exothermicity of the reaction is most conveniently controlled by diluting the diazonium salt with a solid inert medium such as sea sand. In addition to the danger to the experimenter, the reproducibility of the reaction yield is quite poor. The resulting diazonium salt solution is subsequently thermolyzed at 55— hC [55c, 78, 79] Scheme 2. HCl, NaNO2 2. Starting from the corresponding phenol a fluoroformate is generated by reaction with carbonyl chloride fluoride and subsequently catalytically decarboxylated to the aryl fluoride, in the gas phase, by contact with hot platinum [80] Scheme 2.

In this the fluoroformate is formed by the catalyzed reaction of the phenol with CO2 in HF, and the expensive platinum catalyst is replaced by an aluminum-based material. Under optimized conditions, depending on the nature of the substituents X, the yields are nearly quantitative [80]. HF The thermodynamic force driving this process is the formation of water as the only stoichiometric byproduct. The intermediately formed CuF2 acts as the fluorinating agent at temperatures around hC.

The resulting copper is subsequently recycled by reaction with hydrofluoric acid and oxygen at hC. The reaction—regeneration cycles can be repeated without loss of activity of the copper reagent. The same process can also be used for the waste-efficient and cost-effective industrial production of other fluorinated arenes such as fluorotoluenes and difluorobenzenes. The Halex Process The technically most relevant method for synthesis of specifically fluorinated aromatic compounds is the Halex halogen exchange process [82].

Aromatic starting materials with electron-withdrawing substituents, for example halogen or, sometimes, nitro groups are treated at moderate to high temperatures with inorganic 2. Lipophilic phase transfer catalysts PTC , such as tetrakis dimethylamino phosphonium salts [33—38] can increase the efficiency of the exchange reaction dramatically. With the aim of increasing the nucleophilicty of the inorganic fluoride and thus also the efficiency of the process, lipophilic phase-transfer catalysts are often used [33—38] Scheme 2.

Think Negative! Most unsaturated systems, for example perfluoroolefins and perfluoroarenes, are on the other hand, very reactive species. In the same way as the positively charged proton is the key species in olefin chemistry, the negative fluoride ion is its counterpart in perfluoroolefin chemistry Scheme 2. Analogously, but in contrast with hydrogen-based chemistry, perfluoroolefins tend to add nucleophilic reagents, followed either by quenching of the resulting perfluorocarbanion with a suitable electrophile or by re-aromatization with elimination of a fluoride ion Scheme 2.

In perfluoroolefins the situation is more complex — because of the strong inductive effect of the electronegative fluorine, the negative charge density is concentrated in the periphery surrounding the p-system, making its center, with a positive partial charge, most susceptible toward nucleophilic attack by negatively charged nucleophiles. The electrostatic potentials for both compounds are depicted in Figure 2. The p-system is, in addition, destabilized by a repulsive interaction between the lone electron pairs on the fluorine atoms and the p-orbitals on the sp2 hybridized carbon atoms.

Nucleophilic attack on the carbon induces re-hybridization to the sp3 state, relieving some of this repulsive strain. Another contribution to the driving force for nucleophilic addition of fluoride ions is stabilization of the resulting geminal difluoromethylene group by hyperconjugation. The photochemically induced Scheme 2. The reason for this unexpected behavior is that deprotonation would create one more fluorinated sp2 center.

In contrast, the expected behavior is observed for the pentakis trifluoromethyl derivative, which is more acidic by 16 orders of magnitude [91]. Aromatic Nucleophilic Sustitution The destabilization of sp2 -bound fluorine by p—p repulsion activates fluorinated aromatic compounds toward nucleophilic attack and subsequent substitution. The ease of nucleophilic halogen replacement — F i Cl i Br i I — is in the opposite order to that for aliphatic nucleophilic substitution.

The ease of this replacement increases with the degree of fluorination. Perfluoroaromatic compounds such as hexafluorobenzene or pentafluoropyridine are especially highly reactive toward a variety of nucleophiles Scheme 2. For hexafluorobenzene a second nucleophilic replacement always occurs in the position para to the first substituent. A similar, clear preference is also observed for perfluoronaphthalene [95]. Rationalization of the observed selectivity can be based on several considerations [95]. The negative charge of the intermediate adduct analogous to the s-complex in electrophilic aromatic substitution has to be stabilized.

This 2. F F F quant. This inductive effect must overcompensate the concomitant strongly destabilizing p—p repulsion of the sp2 -bound fluorine atoms which is most significant in the positions ortho and para to the site of nucleophilic attack. Most effective for overall stabilization of the negatively charged intermediate Scheme 2. The negatively charged primary addition product is stabilized best by fluorine in the ortho position o , second best in the meta m , and least in the para position p.

OMe, NMe2 [95]. Systematic exploitation of the different susceptibilities of the different positions of perfluoroaromatic compounds can be used as a tool for combinatorial synthesis of fluoro aromatic compounds. The feasibility of this concept was recently demonstrated by R. Chambers and coworkers who used the pentafluoropyridine system as an example [99] Scheme 2. Further differentiation of the reactivity toward hard and soft nucleophiles was achieved by partial replacement of fluorine by bromine in this system.

Br quant.

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Nevertheless, activation of the C—F bond in highly electron-deficient compounds such as 2,4,6-trifluoropyrimidine, pentafluoropyridine, or hexafluorobenzene is possible with stoichiometric amounts of bis triethylphosphano nickel 0 [] Scheme 2. More recently Herrmann and coworkers [] have described a variant of the Kumada—Corriu cross-coupling reaction [] between fluorobenzene and aryl Grignard compounds which uses catalytic amounts of nickel carbene complexes. Hammett analysis of the relative kinetic rate constants indicated that the reaction proceeds via initial oxidative addition of the fluoroaromatic reactant to the nickel 0 species.

Above: stoichiometric reaction of electron-deficient fluoroarenes with Ni 0 complexes []. Below: Ni 0 carbene-catalyzed Kumada—Corriu coupling between fluoroarenes and aryl Grignard compounds []. The metal atom — usually lithium — is also stabilized by favorable electrostatic and electron-donating interactions with the lone electron pairs of neighboring groups Scheme 2. The observed ortho selectivity of the metalation of suitably substituted aromatic compounds is, therefore, usually kinetically induced []. In biphenyl systems, the site-directing effect can also result in clean lithiation at the ortho position of the neighboring phenyl ring [].

The reaction product is stabilized by interaction of the lone electron pairs of the group X with the neighboring lithium [, ]. Fluorine is also highly effective as a strongly ortho-directing, acidity-enhancing substituent []. Whereas many aryl lithium species are stable up to room temperature and above, ortho-fluoro lithio arenes are stable at low temperatures only. Ortho-Metalation is a tool of high value not only for derivatization of fluorinated arenes — the aryl lithium species can subsequently be converted into a variety of useful synthetic intermediates. Choice of the right combination of base and solvent enables highly selective derivatization of halogenated arenes; this cannot yet be achieved by any other means [] Scheme 2.

The primary metalation product with no ortho-directing neighbor or one only can gain additional stability by transmetalation, leading to a product with two stabilizing ortho substituents. This effect is more likely in strongly coordinating solvents, for example THF, and can be suppressed by changing the reaction medium to diethyl ether, which leads to higher aggregation and lower reactivity of the metal organic species []. If additional stability can be gained, e. Occasionally bottom this can be suppressed by the right choice of reaction solvent [].

Pd PPh3 4, 2 N aqu. In such circumstances a protective group strategy is necessary to temporarily block the most acidic positions of the intermediates. A convenient group for traceless aromatic blocking is the trimethylsilyl group, which is readily removable by use of inorganic fluorides e. Despite this and other early failures, a variety of successful and convenient strategies designed to solve this general synthetic problem have been developed, especially since the s. Afterwards, the same principal method was used to obtain ethyl fluoride [] and other alkyl fluorides. Nowadays, activation of alcohols with more nucleofugic leaving groups, for example mesylate, tosylate or triflate, and subsequent nucleophilic SN2 substitution by fluoride under clean inversion, have become a standard tool, particularly when fluorination with defined stereochemistry is required Scheme 2.

This ion, in turn, effects nucleophilic replacement of the now present leaving group. Stereochemically, this process results in clean inversion at the carbon center. The first examples of this kind were the a,a-difluoroalkylamine reagents introduced by Yarovenko [] and Ishikawa []. They are conveniently obtained by reaction of dimethylamine with either chlorotrifluoroethylene or perfluoropropene, respectively, and are quite effective for conversion of aliphatic alcohols to alkyl fluorides Scheme 2. Another useful addition to the methodic toolbox was the more stable a-fluoroenamine reagent introduced by Ghosez and coworkers [] which enables several highly selective conversions Scheme 2.

An advantage of this reagent is that it acts in a neutral reaction medium, thus also enabling transformation of acid-sensitive substrates. Top: the per- fluoropropene-based reagent exists as an equilibrium mixture of an a,a-difluoroalkylamine and the two isomeric a-fluoroenamines. Middle: The dimethyl 2-chloro-1,2-difluorovinyl amine reagent has a more defined composition.

Bottom: Synthesis of an a-fluoroenamine fluorination reagent [—]. The mechanism of the primary condensation Scheme 2. Addition of the alcohol coverts the sp2 center into a very electron-rich sp3 center and the fluoride ion is expelled, facilitated by the combined p-donation from the dimethylamino and alkoxy groups. The resulting imido ester is, in turn, a nucleofugic leaving group which is replaced by the fluoride ion. The most significant side-reactions with all a-fluoroenamine reagents are elimination and, in allylic systems, rearrangements. Examples of the fluorination of alcohols with a,a-difluoroalkylamines or a-fluroroenamines.

Synthesis of cycloalkyl fluorides, fluorosteroids, fluoroterpenes, and glycosyl fluorides with a-fluoroenamines [, ]. The SN2 mechanism of the replacement of the imidoester leaving group by the fluoride ion results in a clean inversion. By reaction with the inexpensive phosgene and subsequent nucleophilic fluorination the reagent can be recycled on an industrial scale. Sulfur Tetrafluoride and DAST Probably the most versatile reagent for one-step exchange of hydroxy groups by fluorine, and for many other conversions, is sulfur tetrafluoride SF4 []. Sulfur tetrafluoride first converts the alcohol into a covalent intermediate with a nucleofugic group which is subsequently replaced by a liberated fluoride ion, with inversion SN2 mechanism.

The sulfur tetrafluoride is converted into sulfonyl fluoride, only two fluorine atoms are used for the reaction. It is a highly toxic gas m. In order to overcome these difficulties, less volatile analogs of SF4 have been synthesized by exchanging one fluorine atom by a dialkylamino group Scheme 2. Because of the relative instability of the sulfur—nitrogen bond, DAST can explode violently when heated over ca 50 hC.

Frequently occurring side-reactions are elimination and rearrangements of the carbon skeleton [], because of the intermediate formation of carbocationic species.

With the aim of obtaining a fluorination reagent which can be safely handled on a larger scale, other derivatives such as the morpholino sulfurtrifluoride MOST or the methoxyethyl analog Deoxofluor were developed []. Deoxofluor also decomposes at elevated temperatures, but it does so without a thermal run-away reaction 61 62 2 Synthesis of Complex Organofluorine Compounds and subsequent explosion. This renders the reagent safe enough for application in the industrial production of fluoropharmaceuticals and advanced materials.

The lower reactivity of DAST and its analogs compared with SF4 can be attributed to its larger steric requirements and to the less strong inductive effect of the dialkylamino moiety. This is obvious from failed attempts to fluorinate hydroxy groups in sterically crowded positions [] Scheme 2. The desired effect was observed, but not to a preparatively useful extent. This type of reaction in an acidic medium proceeds via a stabilized carbocation by an SN1 mechanism. Fluoride addition is often reversible, and the stereochemistry of the reaction is controlled thermodynamically only by the relative free enthalpies of the possible product isomers.

Thus, glycosyl fluorides can be conveniently prepared from a variety of different glycosidic precursors, because of the stability of the intermediately formed glycosyl cation [, ] Scheme 2. The reactivity of SF4 is further enhanced by addition of Lewis acid catalysts for example BF3 or simply by conducting the reaction in aHF as solvent.

Dmowski postulated a mechanism for the reaction []. A fluorine atom is then transferred intramolecularly to the carbon and sulfonyl fluoride is expelled. The formation of typical by-products, mostly rearrangement products, can be explained on the basis of this mechanism. The more convenient reagent DAST can also be used to fluorinate aldehydes and some ketones in high yields Scheme 2. The reaction does not work for sterically hindered ketones or for esters or anhydrides, even under harsh conditions. As in the fluorination of alcohols, here also the most important side-reactions are elimination and rearrangements.

As demonstrated for pivaldehyde as example Table 2. Table 2. Carboxyl into Trifluoromethyl The conversion of carboxyl groups into trifluoromethyl groups proceeds in two steps. The first step, exchange of the hydroxy group by fluorine, can be accomplished easily by use of less potent fluorination agents such as a-fluoroenamines or DAST.

Subsequent conversion of the carboxylic acid fluoride into the trifluoromethyl group requires more drastic conditions and can be achieved only with SF4. The most convenient procedure is the one-step direct reaction of carboxylic acids with SF4 in aHF as solvent Scheme 2. For most aliphatic and aromatic carboxylic acids, excellent yields can be obtained even at room temperature or below. A major side-reaction of the fluorination of carboxylic acids is the formation of bis a,a-difluoroalkyl ethers, presumably Scheme 2. The principal method was initially discovered in the s [, ]; since the beginning of the s it has been systematically developed into a valuable tool for fluoroorganic synthesis [—].

The general concept is that sulfur is introduced into the organic substrate as a direct synthetic precursor of fluorine. The chemical oxidant can also be replaced by electrochemical oxidation [, ]. The sulfur species is thus activated by S-halogenation into a nucleofugic leaving group, which is substituted by fluoride. The fluorodesulfuration of thiocarbonyl compounds is supposed to follow a similar principal pathway.

The mechanism as depicted in Scheme 2. The extruded sulfur species cannot be expected to be stable in the presence of a substantial excess of oxidant and the typical subsequent aqueous work-up conditions. Many varieties of fluorodesulfuration of protected or activated carbonyl compounds are known. Some contain an intermediate reductive step, leading to a mono-fluoromethylene instead of a gem-difluoromethylene group []. It has been demonstrated several times that different sulfur species thiocarbonyl or thioether can be selectively oxidized by careful choice of thiophilic oxidant and the acidity of the reaction medium.

It seems that after oxidation of the thiocarbonyl group the resulting gem-difluoromethylene moiety deactivates the remaining sulfur against further thiophilic attack. Orthogonal glycosidic activation is an important step in the direction of automated oligoglycoside synthesis [].

To facilitate purification, a hydrophobic tag e. Conditions A are for thioglycoside activation, conditions B for activation of glycosyl fluorides. The methodology enables convenient access to aliphatic trifluoromethyl ethers and, more recently, to a,a-difluoroalkyl [a] and perfluoroalkyl ethers also [] Scheme 2. NaH, THF 2. CS2 3. The alkoxydifluorodesulfuration of dithianylium salts [] has some very special advantages compared with other known fluorodesulfuration routes via thionoesters [].

They can be either prepared from carboxylic acids or acid chlorides [] and isolated by simple precipitation as stable, crystalline solids. Making use of the reversibility of the formation of aliphatic dithianylium salts the thermodynamically preferred transalkylcyclohexyl dithianylium salts can be conveniently obtained by protonation and subsequent equilibration of the corresponding ketenedithioketals. The in situ formation of dithianylium salts by protonation of ketenedithioketals is also quite useful for generation of simple 2-alkyl-1,3-dithianylium salts which do not crystallize.

Mechanistically the only difference from the chemistry depicted in Scheme 2. For alkyl or aryl dithianylium salts with less fluorination the dithioorthoester is a labile intermediate which is only stable at low temperatures up to ca. This intermediate is subsequently fluorodesulfurated to yield the corresponding a,a-difluoroether.

H11C5 in situ generation 1. F H H11C5 CF2O F H F Dithianylium salts in combination with oxidative fluorodesulfuration chemistry are also useful reagents for synthesis of gem-difluoromethylene analogs of carboxylic acid derivatives other than esters. If the fluorodesulfuration is conducted in the presence of other O- or N-nucleophiles the corresponding a,a-difluoroalkyl compounds are obtained in reasonable to good yields Scheme 2. As the key step of this enzymatic reaction sequence a trialkylsulfonium ion SAM reacts with inorganic fluoride in a nucleophilic replacement with methionine as the leaving group.

C3H7 2. One valuable component still missing from the toolbox of methods in organofluorine chemistry was a generally applicable method for electrophilic fluorination of sensitive organic substrates under mild conditions. Xenon Difluoride One of the first reagents used for electrophilic fluorination was xenon difluoride XeF2 [], a solid which is easy to handle and which can be used in solvents which are relatively inert toward oxidation, for example acetonitrile and dichloromethane. The reactivity is mostly determined by its strong oxidizing power, rendering its mode of action more oxidative than electrophilic fluorination.

It was used commercially from the beginning of the s for production of fluoropharmaceuticals, in particular fluorosteroids. FClO3 owes its reactivity to the fluorine bound to a strongly electronegative chlorine in its highest oxidation state. Although FClO3 enables selective synthesis of complex organic compounds such as fluorocorticoids Scheme 2. Oleg V. Victor Starov. Green Solvents II. Ali Mohammad. Principles of Asymmetric Synthesis. Robert E. Csaba Visy. Applications of NMR Spectroscopy.

Jeffrey H. Advances in Heterocyclic Chemistry. Eric Scriven. Sulfur-Containing Reagents. Leo A. Directed Selectivity in Organic Synthesis. Tanja Gaich. Hypervalent Iodine Chemistry. Viktor V. Silicon Polymers. Aziz M. Metal-Catalyzed Reactions in Water. Pierre Dixneuf. Steric and Stereoelectronic Effects in Organic Chemistry. Veejendra K. Basics of Flow Microreactor Synthesis.

Jun-ichi Yoshida. Advances in Elastomers II. Thomas E. Mid-size Drugs Based on Peptides and Peptidomimetics. Hirokazu Tamamura. Reviews in Fluorescence Chris D. How to write a great review. The review must be at least 50 characters long. The title should be at least 4 characters long. Your display name should be at least 2 characters long. At Kobo, we try to ensure that published reviews do not contain rude or profane language, spoilers, or any of our reviewer's personal information. You submitted the following rating and review. We'll publish them on our site once we've reviewed them.

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