Section 4. Fluorine Compounds

He has published more than 100 research papers and holds 25 patents. He has written three books, one of them ACS Monograph 155, Aromatic Fluorine Compounds, in 1963. In 1976, he received the ACS California Section Award for Outstanding ConUibution to Chemistry for his work of a quarter century on various aspects of fluorine chemistry. In addition to his scientific activities, he is also serving his second term on the ACS Board nf ri... 

A number of preparations of mixed halogenophosphoranes from tervalent phosphorus-fluorine compounds have been reported. For example, acyclic and cyclic fluorine compounds have been converted to phosphoranes, such as (36) and (37), by treatment with chlorine. Similar reactions leading to AA-dialkylaminodichlorodifluorophosphoranes (38) have been described and the stability of (38) to exchange processes commented upon. iVA-Dialkylaminotetraiodophosphoranes (39) have been prepared from AA-dialkylaminodichlorophosphines and lithium iodide, although no detailed physical evidence for the structure of these unusual compounds has yet been reported. The preparation of bis-(A-alkylamino)difluorophosphoranes (4) has been described above (see Section lA). 

This section focuses on the preparation of fluorinated compounds through asymmetric hydrogenation/reduction reactions and nucleophilic additions by listing some examples. The first successful example of catalytic asymmetric hydrogenation of a fluoro-compound was reported by Konig et al.81... 

Besides sertraline (no. 10, see Section 3.10) other recently developed antidepressants have become very popular, including two fluorinated compounds, fluoxetine (Prozac , no. 13) and paroxetine (Paxil , no. 14). 

Five- to six-month-old tobacco plants (Nicotiana tabacum var. Samsun) grown in a glasshouse at 20°C were used for this study. Commercial synthetic substrates employed both for histochemical and biochemical assays were guaiacol, p-phenylenediamine-pyrocatechol (PPD-PC), 3-3 di-aminobenzidine (DAB), tetramethylbenzidine (TMB) and syringaldazine. Isopropylamine and monosodium salts of ferulic acid were also used as substrates as well as their / -fluorinated analogues substituted with a fluorine atom on the / -carbon (Fig. 1). Histochemical observations were done on hand-made transverse sections of fresh tobacco stems. Biochemical assays were performed separately on bark (inner cortical parenchyma, phloem and fibres) and xylem fractions. Technical data of incubation, enzyme extraction, spectrophotometric and electrophoretic assays were given elsewhere (5-7). Synthesis of fluorinated compounds was performed as previously described (4). 

One may conclude that the above-mentioned anhydrous [ F]fluorine compounds, except perhaps H[ F]F, have been abandoned, partly because of their limited potential and difficulty of preparation and also because of the success of the main three agents of today, [ F]fluoride (see Section 4), p F]fluorine gas (see Section 3.1.1) and acetyl [ F]hypofluorite (see Section 3.1.3). The advent of the first one, ([ F]fluoride), made less urgent the need for high-specific-activity electrophilic fluorine and the latter two, ([ F]fluorine gas and acetyl p F]hypo-fluorite), are able to perform practically all low-specific-activity electrophilic syntheses (see Section 3), putting a brake on the development of alternatives. 

The fluorinated vinylzinc reagents formed via direct insertion of zinc into the carbon-halogen bond of a vinyl halide have served as useful synthons for the stereospecific synthesis of a wide variety of fluorinated compounds. Some illustrative examples of some of the synthons developed are summarized in the following sections. 

This survey covers the most important information, published after 1960 in monographs, reviews, and papers of completely different nature in approach, experimental pathways and scientific weight and character. Therefore it is, as such, a cocktail of results, ranging from extensive, complete, statistically relevant toxic data of organo-fluorine compounds to the results of mere prescreening experiments. Some classes of compounds, considered to be nontoxic (see Section 5.1.) are, however, excluded. Bearing in mind the protection of scientists and their coworkers, this is the best approach, if conscious of adequate responsibility. This review is written for experimental chemists, rather than toxicologists. 

The Deutsche Forschungsgemeinschaft (DFG) publishes an annual report Maximale Arbeits-platzkonzentrationen (MAK) und Biologische Arbeitsstofftoleranzwerte (BAT) (maximum workplace concentrations and biological materials tolerance levels),20 to protect workers against well-defined and determined toxic or probably toxic materials in workroom air the organo-fluorine compounds included in the 1997 edition are listed in Table 3.20 These data also allow on a representative basis a comparison of acute toxic and safe concentrations of the same species (see also Section 5.2.7-)-... 

This section can provide only a glimpse of the remarkable diversity of the applications for organo-fluorine compounds which have been developed over the past fifty years and readers requiring more details are directed to the more comprehensive reviews which are cited. 

Various fluorine compounds, such as xenon(II) fluoride, act under certain conditions (irradiation, gas-phase reaction) as radical fluorinating agents. Electrochemical fluorinations (see Section 7.) carried out in hydrogen fluoride containing systems (ref 7, pp73-76) are further examples of radical-type reactions. 

The order of reactivity of the halogens is F2 > Cl2 > Br2 > 12. Fluorine is too reactive to be of practical use for the preparation of aromatic fluorine compounds and indirect methods are necessary (see Section 23-1 OB). Iodine usually is unreactive. It has been stated that iodination fails because the reaction is reversed as the result of the reducing properties of the hydrogen iodide that is formed ... 

Side-chain fluorine compounds with the groupings —CHF3, —CF2—, and —CF3 are available by the reaction of sulfur tetrafluoride or molybdenum hexafluoride with carbonyl compounds (see Section 16-4D) ... 

Warning. Many of the nitrogen-fluorine compounds discussed in this section are very hazardous materials. Their syntheses should not be undertaken without adequate shielding equipment and a prior knowledge of techniques for the handling of explosive substances. Compounds of this type are labeled extra-hazardous or hazardous, depending upon properties of the material. 

The majority of the more important methods for the preparation of fluorinated compounds by substitution reactions have been reviewed in the previous sections. There are, however, some additional important synthetic procedures which should also be mentioned, mainly those concerned with the introduction of fluorine by substitution of functional groups containing boron, silicon and tin the reactions of organotin compounds are the most well-studied to date. These reactions are excellent synthetic methods for obtaining vinyl and aryl fluorides (sec also Section 1.1.1.1.). 

Very little quantitative data on other hydrogen-halogen systems is available. The H2-F2 reaction is discussed in section 7 (Reactions of fluorine compounds) and the only other quantitative data on these systems is for the H2-ICI reaction. 

A142. M. Hudlicky, Chemistry of Organic Fluorine Compounds. Pergamon, Oxford, 1962. 536 pp. A short section (14 pp.) deals with organometallic compounds. 

This part of the discussion can be divided into two sections, depending on whether fluorine is introduced into the preformed heterocycle or whether the heterocyclic system is formed by cyclization involving an already fluorinated compound. 

The dominant source of fluorine compounds as precursors for systems that will take part in these cyclizations are the fluorocarbon carboxylic adds. Many of these compounds are available through electrochemical fluorination processes (Eq. 40),157 which are carried out on an industrial scale. These can then be converted to standard derivatives which are employed in the various ways described in this section. 

This section discusses how the fluorine atom influences the physical and physicochemical properties of organic fluorine compounds. One of the most important factors for a better understanding of such properties would be the low electronic polarizability (refractive index) of the molecules. Of course, we cannot disregard other effects such as the strong electron-withdrawing effect and stiff nature of the perfluoroalkyl moiety. 

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