Diazonium salts fluorination

Substitution of an aromatic amino group by fluorine via a diazonium salt using fluoroborates... 

In fluorinated alcohols such as 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-isopropanol, only alkoxy-de-diazoniation and substitution by the anion of the diazonium salt are observed (Sec. 8.3), because these alcohols are extremely weak nucleophiles. 

Research on the fluorination of aromatic amines has provided access to 4-fluoro-2,l,3-benzo-thiadiazole (77). Treatment of 4-amino-2,l,3-benzothiadiazole (1) with nitrosonium tetra-fluoroborate (NOBF4), followed by heating of the resulting diazonium salt, gave the aryl fluoride (77) in 23% yield <92SC73>. 

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... 

In contrast, some substituted anilines, e.g. 2-nitroaniline,143 2-chIoro-4-(trifluoromethyI)ani-Iine,143 benzene-1,3-diamine,150 or 4-chlorobenzene-1,3-diamine,150 give only very low yields of product or formed tars under the fluorination conditions. The diazotization followed by in situ fluorodediazoniation of the corresponding diazonium salts have been systematically studied in hydrogen fluoridc/base solutions of different composition to ascertain the most important influences on the reaction.329 Besides numerous examples of substituted anilines, various derivatives of pyridine, pyrimidine, 1.3,5-triazine, and benzthiazole have been included in these investigations (yields 45—99%). 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

As diazonium tetrafluoroborates are more soluble in strongly acidic media, the precipitation of the diazonium tetrafluoroborate from an auxiliary diazonium salt and alkaline tetrafluoroborate is preferred when the diazonium tetrafluoroborate is thought to be too soluble an increase of the ionic strength tends to decrease its solubility.3-129 However, some alkaline chloride can co-precipitate with the diazonium tetrafluoroborate. Consequently, the diazonium tetrafluoroborate yields can be a little optimistic and some chlorinated aromatics can be produced together with fluorinated aromatics during the dediazoniation step.3,171 To prevent such contamination, the diazonium tetrafluoroborate is washed with the minimum amount of chilled water, then with another polar solvent, such as an alcohol, and finally with a water-insoluble solvent, such as diethyl ether. When their decomposition points are not too low, diazonium tetrafluoroborates can also be purified by rccrystallization (in water or acetic acid) or by dissolution in acetone then salting out with diethyl ether.3... 

Traditionally, diazonium tetrafluoroborates are decomposed neat in the solid state. This solid, placed in a flask with large outlets and which must not be more than half full of the salt, is gently heated near its surface until decomposition starts. Often no more heat is required, the decomposition continuing spontaneously with evolution of dense vapors of boron trifluoride. The reaction medium is often brought to dull redness and the fluorinated product distills if sufficiently volatile.1,3 The filled reaction flask can also be immersed in a fluid brought to ca. 20 to 50 C above the decomposition temperature of the diazonium salt, previously determined in a capillary tube.1,3,200,201 In another procedure, the reaction flask can be heated to this temperature while empty, then the diazonium tetrafluoroborate is added little by little 200-201 This latter method has been adapted to perform the decomposition of diazonium tetrafluoroborates in a continuous way by two techniques ... 

Diazonium salts can also be decomposed under reduced pressure in order to distill relatively unstable fluorinated products as soon as they are formed.1,203,204... 

It has been demonstrated that the presence of chlorine or bromine in the nucleus facilitates replacement of the diazo group by hydrogen little or no ether formation occurs.26 Apparently iodine also favors the redudng action of alcohols, but this point has not been investigated carefully.26 27 No attempts to deaminate fluorinated amines are recorded. Representative of the effitiency with which ethanol reduces diazonium salts derived from halogenated amines are the deaminations of m-chloroaniline 26 (87% yield), of 2-bromo-4-methylaniline 28 (67% yield), of 2,4,6-tribfomoaniline 29 (ca. 80% yield), and of 2-carboxy-4-iodoaniline30 (ca. 45% yield) in the biphenyl series the deamination of VIII in 53% yield 31 may be dted. 

The best results have been obtained in the non-polar solvents heptane or 0-xylene. Polar aprotic solvents such as Me2CO, MeCN, DMSO or dioxane gave poor yields and byproduct formations. Water-free conditions to avoid hydrolysis of BC14- have been necessary. The best fluorination yields have been achieved in the 373-393 K temperature interval (in 0-xylene with TBAF, tetrabutylammonium fluoride). An increase in the yield was observed if an excess of the diazonium salt was used. The total labelling procedure took 50 min. The tetrachloroborate incorporates fluoride by a halide exchange reaction (equation 3)9 10. 

The most widely used method for the substitution of nitrogen-containing functional groups by fluorine is the thermal or photochemical decomposition of diazonium salts, the Baltz-Schiemann reaction (see Section 1.1.8 ). 

SAFETY PROFILE Poison by intravenous route. Moderately toxic by ingestion and intraperitoneal routes. Human teratogenic effects by ingestion developmental abnormalities of the endocrine system. Experimental teratogenic and reproductive effects. Mutation data reported. Explosive reaction with charcoal + ozone, trifluoroacetyl hypofluorite, fluorine perchlorate. Violent reaction or ignition on contact with diazonium salts, diisopropyl peroxydicarbonate, bromine pentafluoride, chlorine trifluoride. Incompatible with oxidants, BrFs, FCIO, metallic salts, calomel. When heated to decomposition it emits very toxic fumes of K20 and I . See also IODIDES. 

A diazonium salt reacts with fluoroboric acid (HBF4) to form an aryl fluoride. This is a useful reaction because aryl fluorides cannot be produced by direct fluorination with F2 and a Lewis acid catalyst, as F2 reacts too violently (Section 18.3). 

One of the earliest means of introducing fluorine selectively into specific positions of aromatic compounds is the Balz-Schiemann reaction [77] which dates back to the 1920s. An isolated arene diazonium tetrafluoroborate is thermolyzed at up to 120 °C 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. 

---