The Balz-Schiemann Reaction

The Balz-Schiemann reaction, the classic synthesis of fluoro-aromatic compounds, involves diazotisation of an aromatic amine, isolation of the diazonium fluoroborate or hexafluorophosphate, then thermal decomposition of the dry salt, usually diluted with sand for safety. It is a useful method, with application to a number of heterocyclic systems, for example methyl 3-aminothiophene-2-carboxylate.  

An industrial method involves diazotisation in anhydrous HE This hazardous method has advantages for large-scale production, but is not suitable for normal laboratory-scale work  

A variation on the standard reaction avoids isolation of the diazonium salt by its generation, under anhydrous conditions, at its decomposition temperature. The only heterocyclic example so far described is the preparation of 3-fluoroquinoline, but the method could no doubt be applied to other systems. 

A method using polyvinylpyridinium hydrofluoride (PVPHF), as fluoride source, at low temperature was suitable for the relatively sensitive 2-deoxy-nucleosides. This low temperature reaction was probably successful due to the instability, i.e. high reactivity, of diazonium salts at the a-position of azines, and may not be general for other heterocycles. 

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Fluoronaphthalene [323-09-1] is prepared in 54—67% yield from 2-naphthylamine by the Balz-Schiemann reaction or in 51% yield by pyrolysis of indene and chlorofluoromethane at 600°C (77). 

Difluoronaphthalene [315-52-6] is prepared from 4-fluoro-l-naphthylarnine by the Balz-Schiemann reaction. 1,4-Difluoronaphthalene is used in chemical carcinogenesis studies as a synthon for highly condensed difluoro—polycycHc aromatic hydrocarbons (273). 

New diazotization techniques for the Balz-Schiemann reaction feature alter native mtrosating agents in place of aqueous sodium nitrite or substitution of other salts such as arenediazonium hexafluorophosphates for arenediazoniuin fluoroborates... 

The Bergmann variation of the Balz Schiemann reaction is a two-step process featuring copper- or copper halide-catalyzed decomposition of aqueous or acetone solutions of arenediazonium fluoroborates containing alkyl or halogen substituents [30] A recent modification is a one-step technique featuring simultaneous diazoti-zation and decomposition by addition of aqueous sodium nitrite at 25 °C to a mixture of fluorobonc acid, copper powder, and 2 isopropyl 6 methylaniline to give 2-isopropyl-6 methylfluorobenzene in 73% yield [37]... 

The discovery of the Balz-Schiemann reaction in 1927 replaced the earlier Wallach procedure (1886) based on fluorodediazoniation of arenediazonium piper-idides (aryltriazenes) in aqueous hydrogen fluoride [40 41]... 

The preparation of an aryl fluoride—e.g. fluorobenzene 3—starting from an aryl amine—e.g. aniline 1—via an intermediate arenediazonium tetrafluoroborate 2, is called the Schiemann reaction (also called the Balz-Schiemann reaction) The diazotization of aniline 1 in the presence of tetrafluoroborate leads to formation of a benzenediazonium tetrafluoroborate 2 that can be converted into fluorobenzene 3 by thermolysis. 

The Balz-Schiemann reaction continues to attract attention, with much of it generated by the interest in fluoroquinolones, e.g., (7), which is a potential antibacterial. Two approaches to its synthesis are possible—introduction of fluorine prior to or post ring construction. Decomposition of the tetrafluoroborate salt was unsuccessful, whereas the PF6 salt (8) gave only a poor yield (84JMC292). A more successful approach was the introduction of F into the pyridine nucleus prior to formation of the 1,8-naphthyridine ring (84JHC673). A comparison of decomposition media showed that cyclohexane was the best with regard to yield and time. 

Photochemical modification of the Balz-Schiemann reaction has enabled fluorine-containing biologically important molecules e.g., imidaz-... 

On the basis of these redox potentials it seems likely that direct electron release to the benzenediazonium ion takes place only with iodide. This corresponds well with experience in organic synthesis iodo-de-diazoniations are possible without catalysts, light, or other special procedures (Sec. 10.6). For bromo- and chloro-de-di-azoniations, catalysis by cuprous salts (Sandmeyer reaction, Sec. 10.5) is necessary. For fluorination the Balz-Schiemann reaction of arenediazonium tetrafluoroborates in the solid state (thermolysis) or in special solvents must be chosen (see Sec. 10.4). With astatide (211At-), the heaviest of the halide ions, Meyer et al. (1979) found higher yields for astato-de-diazoniation than for iodo-de-diazoniation, a result consistent with the position of At in the Periodic System. It has to be emphasized, however, that in investigations based on measuring yields of final products (Ar-Hal), the possibility that part of the yield may be due to heterolytic dediazoniation is very difficult to quantify. 

Milner (1992) recently described a novel and versatile modification of the Balz-Schiemann reaction. The amine is diazotized with solid nitrosonium tetrafluoro-borate in CH2C12 and, without isolation, the diazonium salt is heated and yields the fluoroarene in good yield. The method is also applicable to aniline derivatives bearing carboxy and hydroxy substituents, compounds which give poor yields in the classical procedure. 

Mechanistically there is ample evidence that the Balz-Schiemann reaction is heterolytic. This is shown by arylation trapping experiments. The added arene substrates are found to be arylated in isomer ratios which are typical for an electrophilic aromatic substitution by the aryl cation and not for a homolytic substitution by the aryl radical (Makarova et al., 1958). Swain and Rogers (1975) showed that the reaction takes place in the ion pair with the tetrafluoroborate, and not, as one might imagine, with a fluoride ion originating from the dissociation of the tetrafluoroborate into boron trifluoride and fluoride ions. This is demonstrated by the insensitivity of the ratio of products ArF/ArCl in methylene chloride solution at 25 °C to excess BF3 concentration. 

Fluoroarene formation from arylamines. Also known as the Balz-Schiemann reaction. 

In order to use the potentiality of the Balz Schiemann reaction and to increase the specific radioactivity, the tetrafluoroborate anion was substituted for the tetrachloroborate. The fluorination of p-toluidyl diazonium tetrachloroborate. 

The Balz-Schiemann and Wallach reactions The Balz-Schiemann reaction (the thermal decomposition of an aryl diazonium salt. Scheme 46) was for many years the only practical method for the introduction of a fluorine atom into an aromatic ring not bearing electron-withdrawing substituents. This reaction, first reported in the late 1800s, was studied in fluorine-18 chemistry as early as 1967 [214]. It involves the generation of an aryl cation by thermal decomposition, which then reacts with solvent, nucleophiles or other species present to produce a substituted aromatic compound. Use of fluorine-18-labelled... 

The Wallach reaction, the thermal decomposition of an aryl triazene (Scheme 46), has also been attempted as an alternative to the Balz-Schiemann reaction [54,220,221]. Although a wide variety of experimental conditions have been tried, the radiochemical yields remain low. 

Aromatic fluorination involves analogous methods to those used in the aliphatic series. The most utilized methods are electrophihc fluorination (F2, N— F reagents) and nucleophilic fluorination through the Balz-Schiemann reaction (diazotation in the presence of fluoride ion). This latter method is of prime importance in industry. When the aromatic ring is activated by one or several electron-withdrawing groups, the... 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

Two routes to the electrophilic fluorination of pyrrolo[2,3-3]pyridine A -oxide lead to the 4-fluoro derivative. The Balz-Schiemann reaction route, via a diazonium tetrafluoroborate salt, or a lithium/halogen-exchange reaction followed by quenching with an electrophilic fluorine source, generates the 4-fluoro product in moderate yields <20030L5023>. 

A simple example of the Balz-Schiemann reaction is the preparation of 2-fluoropyridine by diazotization of 2-aminopyridine in HF-pyridine at 0°C, and then allowing the salt to warm up to 20°C [88JFC(38)435] there are many other examples [81CJC2608, 81JOC4567 82JHC1245 84H(22)1105 85H(23)1431, 85H(23)1969, 85JHC145 87LA857]. Chloro,... 

The second product in this reaction, the difluorotris(perfluoroalkyl)-A5-phosphane, does not dissolve in aryl fluorides and, because of its greater density, forms a lower layer which can be easily separated. In this way the difluoro-A5-phosphanes are regenerated almost quantitatively and can be used in the synthesis many times. An example is the decomposition of 4-nitrobenzene-diazonium trifluorotris(heptafluoropropyl)phosphate at 87 C which provides l-fluoro-4-ni-trobenzene in 82% yield and difluorotris(heptafluoropropyl)-A5-phosphane in quantitative yield.6 This method is a convenient modification of the Balz-Schiemann reaction (see Section 26.1.3.). 

Dediazoniation itself is not dramatically dependent on the hydrogen fluoride/pyridine ratio, as shown from the dediazoniation of benzenediazonium tetrafluoroborate (previously isolated) in hydrogen fluoride/pyridine mixtures provided that the hydrogen fluoride/pyridine ratio is larger than 6, fluorobenzene is always obtained in quantitative yield (for hydrogen fluoride/ pyridine ratios below 6, byproducts result from the phenyl cation and free pyridine).10 These observations have resulted in new, very efficient syntheses of 4-fluorophenols 2 involving dediazoniation, in hydrogen fluoride/pyridine mixtures, of crystalline 4-hydroxy benzenediazonium chloride and tetrafluoroborate 3 (formed under anhydrous conditions)89,96 as well as quinone-diazide (formed from aminophenol in tetrafluoroboric acid).93,97 Such methods are more efficient than the Balz-Schiemann reaction under standard conditions. 

Due to the corrosive and toxic nature of volatile hydrogen fluoride, the fluorodediazoniation of aromatic and heteroaromatic amines in anhydrous hydrogen fluoride (see Section 26.1.2.), though very efficient, inexpensive and easy to scale up, needs special apparatus and safety measures which are not always available in every laboratory. Thus, the Balz-Schiemann reaction remains the most popular way to substitute aromatic amino groups for fluorine on a laboratory scale. Moreover, special techniques have been developed during the last decade to control formation, storage and decomposition of arenediazonium tetrafluoroborates on a large scale. 

The story of the Balz-Schiemann reaction began with Bart102 who reported in 1913 on the insolubility of arenediazonium tetrafluoroborates which he found insensitive to shocks and friction and could isolate and dry. Then, in 1927, Balz and Schiemann observed that these solids can be thermally decomposed to aryl fluorides with loss of boron trifluoride.103 This paper was the starting point of intensive research which led, before the 1940s, to almost all the still-valid principles governing this method.104-119 Thus, Roe was able to provide, as early as 1949, a splendid detailed review1 which is still beneficial nowadays. Two other updated reviews were published in the 1960s (see Houben-Weyl, Vol. 5/3, pp 213-246).3... 

The effect of ultrasound on the course of the Balz-Schiemann reaction has been studied using benzenediazonium tetrafluoroborate.263 In the presence of triethylamine trihydrofluoride in l,l,2-trichloro-l,2,2-trifluoroethane (Freon 113), fluorobenzene is formed in a 92-95% yield under 17 kHz sonication for 8 hours at 40 °C. Without ultrasound, only an 85 % yield is obtained after a reaction time of 16 hours. 

The Balz-Schiemann reaction, thermal decomposition of arenediazonium fluoroborates, is still a favorite approach to the laboratory preparation of fluoro aromatics [16, 17 Caution must be exercised in handling and decomposing mtroarenediazomum fluoroborates and pyridinediazomum fluoroborates because detonations have been reported [J8, 19]... 

The controlled thermal decomposition of dry aryldiazonium fluoroborates to yield an aryl fluoride, boron trifluoride and nitrogen is known as the Balz-Schiemann reaction (Expt 6.77). 

The mechanism of the Balz-Schiemann reaction remains obscure. A possible pathway is shown below ... 

Diazotization procedures. Widely used for the production of aromatic fluorine is the Balz-Schiemann reaction. The approach involves diazotization of the aniline and isolation of the insoluble tetrafluoroborate salt, followed by decomposition under heating conditions (Fig. 32). Initially introduced in 1927 [137,138], it did not achieve commercial utility until the mid-1980s. A modification of the Balz-Schie-mann reaction involves replacing the tetrafluoroborate with other counterions such as a fluorine anion [139],... 

H. Suschitzky, The Balz-Schiemann reaction, Advances in Fluorine Chemistry 4 (1965) 1-27. 

Fluoroalkanes can be obtained by fluoride transfer from complex fluoride anions to carbocat-ions in the nitrosative decomposition of certain aliphatic azides. Several complex nitrosonium salts, such as NO " BF4, NO PF(, , and NO ShF ". " have been used for this purpose. This reaction is similar to the decomposition of arenediazonium tetrafluoroborate salts to form aryl fluorides (the Balz-Schiemann reaction, discussed in Sections 1.1.8.5. and Vol. F 10a, p686ff). in which fluoride is transferred from a very weak nucleophile, such as the complex tetrafluoroborate anion, to an electron-deficient center. 

Since volatile, anhydrous hydrogen fluoride is extremely corrosive and toxic, the fluorodediazo-niatron of aromatic amines with this agent require.s special apparatus and. safety conditions, which are not available in most laboratories. Thus, the decomposition of diazonium tclra-fliioro bo rates, which can be readily prepared from aromatic amines and casier-to-handle tetra-fluoroboric acid, is the commonest fluorodediazoniation process, usually referred to as the Balz-Schiemann reaction (see Vol. E 10a, p 705IT). 

Besides thermal decomposition of diazxvnium tetrafluoroborate salts (fluorodediazoniation), the Balz-Schiemann reaction can be carried out under either photochemical or ultrasonic irradiation. 

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