Direct fluorinations aromatic compounds

The changing perspective on the viability of fluorine as a reagent is illustrated by the fact that many selective fluorinations of substrates [8] containing carbon centres of high electron density have now been described, including a variety of enolate derivatives [71, 72], stabilised carbanions [73, 74], steroids [75] and 1,3-dicarbonyl derivatives [76] (Table 3.2) as well as some aromatic compounds [77]. Fluorinated aminoacids have been obtained by direct fluorination [78] (Figure 3.10). 

Electrophilic Addition to Aromatics. Aromatic compounds are fluorinated with 1 by heating without a solvent to about 100-150 °C, or, for low-boiUng compounds, up to reflux temperature. Activated aromatics, such as anlsole or N-acetylaniline, react smoothly, whereas toluene requires considerably longer reaction times and gives low yields (eqs 9 11). In all cases, the regioselectivities are consistent with an electrophilic addition mechanism ortho- and para-substituted products predominate over the meta-isomers. 1 has recently been used in orthometalation-directed fluorination of aromatics. ... 

Direct Fiuorination of Aromatics. Activated aromatic compounds are fluorinated using Lewis acid catalysis at room (26) temperature. The regioselectivity of the fluorination is in agree-... 

The preparation of aromatic fluorine compounds may be accomplished by direct fluorination or by fluonnation of organometallic intermediates. Tlte ipso fluorination of an aryl organometallic derivative with a positive fluorine reagent allows control over the regioselectivity of the fluorination and offers advantages in the preparation of F-labeled materials [II, 50],... 

Accordingly, for decades scientific investigations have been carried out to achieve the direct fluorination which would be attractive as a one-step synthesis alternative. Although the early reports concerned gas-phase direct fluorinations, the most relevant work in the last three decades was based on contacting fluorine gas with the aromatic compound dissolved in a liquid phase. These attempts at gas/liquid... 

Hessel, V., Ehreeld, W., Golbig, K., Haveekamp, V., Lowe, H., Storz, M., WiLLE, C., Gubee, a., Jahnisch, K., Baerns, M., Gas/liquid microreactors for direct Jluorination of aromatic compounds using elemental fluorine, in Ehreeld, W. (Ed.), Microreaction Technology ... 

Geakauskas, V., Direct liquid-phase fluorination of halogenated aromatic compounds, J. Org. Chem. 34, 10 (1969) 2835-2839. 

Geakauskas, V., Direct liquid-phase fluorination of aromatic compounds,... 

Safety precautions applicable to direct liquid phase fluorination of aromatic compounds are discussed [1]. Attention is drawn to the hazards attached to the use of many newer fluorinating agents [2], In a study of fluorination reactions of hafnium and zirconium oxides by the fluoroxidisers xenon difluoride, chlorine trifluoride and bromine trifluoride, reactivity decreased in the order given [3],... 

Several studies on the direct fluorination of aromatic compounds have been carried out and, although the reaction conditions were not the same in each case, there are several generalisations that can be made [136-143]. 

Direct fluorination, therefore, is not particularly effective for the preparation of mono-fluorinated aromatic compounds from monosubstituted precursors since, in these cases, electrophilic fluorination gives mixtures of isomeric products. However, when there are two or more groups in the aromatic substrate which activate the same carbon atom towards electrophilic attack, as in the case of 4-fluorobenzoic acid (Table 5), then direct fluorination is an efficient method for the preparation of fluoroaromatic compounds (Fig. 57) [148]. 

Dichloro-l-fluoropyridinium triflate (lm)55 has been used for the direct fluorination of biologically important aromatic compounds. Reaction of estra-1.3,5(10)-triene-3,17/ -diol and... 

A somewhat related report in which equally impressive selectivity and yield (60—90%) were obtained Cacou and Wolf have studied the low temperature direct fluorination of aromatic compounds in CC13 F (100). They have established that under appropriate conditions molecular fluorination proceeds on substituted benzenes and tolulenes with similar selectivity and orientation as has been commonly observed for other halogens. For example reaction with nitrobenzene gives 80% meta substitution and reaction with tolulene gives 60% ortho substitution. The conversions were reported in this study and found to average 0.01%. 

Direct Fluorination of Aliphatics and Non-C Moieties The basic limitations of direct fluorinations are similar for aliphatic compounds as discussed already using the example of aromatic derivatives and so is the potential of microreactors. The fluorination of ethyl acetoacetate was carried out in an annular-flow microreactor. 

Methods for the chlorination of secondary amines, secondary amides and imides have been reviewed. Secondary alkylamines can be chlorinated by r-butyl hypochlorite at low temperature, or by sodium hypochlorite or iV-chlorosuccinimide. A(-Bromination and A(-iodination can be brought about using the appropriate halogen, but these N-halodialkylamines are unstable and are rarely isolated. A(-Flu-oroamines and Mfluoroamides are also rare. The A(-fluoroimide (CP3S02)2NF, has, however, been prepared by direct fluorination widi fluorine. It is a stable liquid which shows promise as a fluorinating agent for aromatic compounds. ... 

Direct photoreaction (eq 4) is important only for halocarbons (e.g., aromatic compounds) that significantly absorb radiation at wavelengths >295 nm, the cutoff for solar spectral irradiance at the earth s surface. Because saturated chlorinated and fluorinated organic compounds, including methylchloroform and chlorofluorocarbons, absorb solar radiation very weakly, their direct photoreaction is very slow in the sea and in fresh waters. As discussed in a later section, photoreactions of these compounds may be accelerated by sorption and indirect photoreactions in natural waters. Saturated and olefinic polv-brominated and iodinated organic compounds have long absorption tails that extend beyond 295 nm. Direct photoreaction of such compounds in aquatic environments may be significant. 

Although clean, direct fluorination of aromatic compounds is possible [21], the selectivity of this process is not yet high enough for commercialization. Arenes are best fluorinated in acidic solvents such as sulfuric acid or formic acid, to obtain an electrophilic mechanism (Scheme 2.8). 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 ivith higher or lower fluorine content. 

V. Hessel, W. Ehrfeld, K. Golbig, V. Haverkamp, H. Lowe, M. Storz, C. Wille, Gas/ Liquid Microreactors for direct Fluorination of Aromatic Compounds Using Elemental Fluorine, in W. Ehrfeld (Ed.), Proceedings of the 3rd International Conference on Microreaction Technology (IMRET3), Springer, Berlin, 1999, p. 526. 

One way of process simplification is to make molecular complex compounds out of much simpler building blocks (e.g., by multi-component one-pot syntheses like the Ugi reaction), at best directly out of the elements. Especially in the latter case, this is often quoted as a dream reaction [14]. Typically, such routes have been realized so far with hazardous elements, easily undergoing reaction, but lacking selectivity. One example is direct fluorination starting with elemental fluorine, which has been performed both with aromatics and aliphatics. Since the heat release cannot be controlled with conventional reactors, the process is deliberately slowed down. While, for this reason, direct fluorination needs hours in a laboratory bubble column it is completed within seconds or even milliseconds when using a miniature bubble column operating close to the kinetic limit. Also, conversions with the volatile and explosive diazomethane, commonly used for methylation, have been conducted safely with microreactors in a continuous mode [14]. 

Aromatic fluorinated compounds are of considerable interest for the preparation of biologically active substances. Several fluorination reagents such as CF3OF or F2 require special equipment and experience to handle safely. (CF3S02)2NF (55) is stable for long periods at room temperature and found to be an efficient reagent for nuclear fluorination of aromatic compounds. Typical examples are shown in equation 2939. In addition to the utility in the direct aromatic fluorinations, 55 is also useful in the fluorination of carbon... 

Electrophilic fluorination. Fluorination of aromatic compounds is effective in 98% formic acid or sulfuric acid with a 1 9 mixture of F2-N2 at room temperature. The yield for direct fluorination of 1,3-dicarbonyl compounds by this system varies from 15% to 90%. 

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