Deactivation, arenes

Tnfluoroacetic anhydnde in a mixture with sulfuric acid is an efficient reagent for the sulfonylation of aromatic compounds [44] The reaction of benzene with this system in nitromethane at room temperature gives diphenyl sulfone in 61% yield Alkyl and alkoxy benzenes under similar conditions form the corresponding diaryl sulfones in almost quantitative yield, whereas yields of sulfones from deactivated arenes such as chlorobenzene are substantially lower [44] The same reagent (tnfluoroacetic anhydride-sulfunc acid) reacts with adamantane and its derivatives with formation of isomeric adamantanols, adamantanones, and cyclic sultones [45]... 

Activated arenes (toluene, meta-xylene, naphthalene) undergo acylation, whereas strongly deactivated arenes (nitrobenzene, acetophenone) do not react. On the basis of this information, the transformation was suggested to start with alkylation followed by the acylation step. 

A powerful electrophilic species is obtained from C120 and a strong protic acid xuch as trifluoroacetic acid. This reagent effects exclusive ring chlorination of deactivated arenes in high yield with the usual regioselectivity. 

In most instances these catalysts were not satisfactory in terms of yield, range of substrates and turnover numbers of the catalyst. Additionally, they were mostly efficient only in the case of activated aromatics. In order to develop also Friedel-Crafts acylations of less activated or even deactivated arenes, a new generation of catalysts had to be developed. Here, particularly bismuth(III) triflate [33] and hafnium(IV) triflate in the presence of lithium perchlorate [34] or triflic acid [35] are effective, alternative catalysts actually acylating benzene, toluene and halobenzenes. 

In 2000, Dubac s group reported the microwave-assisted Friedel-Crafts acylation of slightly activated and deactivated arenes under solvent-free conditions with FeCl3 as catalyst. Here, for the acylation of toluene a 90% product yield is obtained after 5 min of irradiation and an overall reaction time of 30 min in the presence of only 5 mol% of FeCl3. A sequential MW irradiation at 300 W afforded the acylation of fluorobenzene with 2 -chlorobenzoyl chloride, with a surprisingly high yield of 92% of 2-chloro-4 -fluorobenzophenone (Scheme 6.11). 

Unsymmetrical iodonium salts. The methods for the preparation of unsym-metrical iodonium salts are also suitable for symmetric iodonium salts, since a preformed or in situ generated aryliodine(III) species coming also from deactivated arenes may react with any arene or derivative of it, provided it is not strongly deactivated. In this way, the dipolic intermediate of Scheme 32 i.e. PhI+I0S03, also formed from PhIO and S03, can serve for the preparation of unsymmetrical iodonium salts [96]. 

About the same time, a similar type of activation was observed in the reactions of nitronium salts.20 Nitronium salts (such as NC>2+BF4 or NC>2+ PF6-) show little or no tendency to react with deactivated arenes or alkanes in aprotic media. However, in fluorosulfuric acid or HF-BF3 solution, nitration takes place giving nitration products even nitromethane (eq 15). 

Friedel-Crafts type reactions of strongly deactivated arenes have been the subject of several recent studies indicating involvement of superelectrophilic intermediates. Numerous electrophilic aromatic substitution reactions only work with activated or electron-rich arenes, such as phenols, alkylated arenes, or aryl ethers.5 Since these reactions involve weak electrophiles, aromatic compounds such as benzene, chlorobenzene, or nitrobenzene, either do not react, or give only low yields of products. For example, electrophilic alkylthioalkylation generally works well only with phenolic substrates.6 This can be understood by considering the resonance stabilization of the involved thioalkylcarbenium ion and the delocalization of the electrophilic center (eq 4). With the use of excess Fewis acid, however, the electrophilic reactivity of the alkylthiocarbenium ion can be... 

Although electrophilic reactions involving dications with deactivated arenes may suggest the formation of superelectrophilic intermediates, there are a number of well-known examples of monocationic electrophiles that are capable of reacting with benzene or with deactivated aromatic compounds. For example, 2,2,2-trifluoroacetophenone condenses with benzene in triflic acid (eq 12).13 A similar activation is likely involved in the H2SO4 catalyzed reaction of chloral (or its hydrate) with chlorobenzene giving DDT (eq 13). 

The nitrilium salt 93 is known to react with activated arenes, but in relatively weak acids (CF3CO2H, Ho —2.7), it does not react with benzene or deactivated arenes. However in 5% SbFs 95% CF3SO3H Hq —18 solution, the nitrilium salt 93 gives with benzene benzophenone in 55% yield (eq 27). 

Related classes of gitonic superelectrophiles are the previously mentioned protoacetyl dications and activated acyl cationic electrophiles. The acyl cations themselves have been extensively studied by theoretical and experimental methods,22 as they are intermediates in many Friedel-Crafts reactions. Several types of acyl cations have been directly observed by spectroscopic methods and even were characterized by X-ray crystal structure analysis. Acyl cations are relative weak electrophiles as they are effectively stabilized by resonance. They are capable of reacting with aromatics such as benzene and activated arenes, but do not generally react with weaker nucleophiles such as deactivated arenes or saturated alkanes. 

Parabanic acid (86) has been shown to produce highly electrophilic species in superacidic CF3SO3H, and the resulting electrophile is capable of reacting with and moderately deactivated arenes.40 The superacid-promoted condensation reaction of parabanic acid with benzene (and other arenes) in CF3SO3H provides satisfactory yields of the 5,5-diarylhydantoins (eq 30),... 

Reaction of acetal 104 with benzene in the presence of CF3SO3H leads to product 107 in high yield. This conversion involves formation of the ammonium-carboxonium dication (105), a reactive dication possessing some 1,3-dicationic character. Reaction with benzene and subsequent loss of methanol generates another reactive dication (106), which then gives the product. The superelectrophilic character of the ammonium-carboxonium dications is indicated by their reactions with moderately deactivated arenes, such as o-dichlorobenzene. 

Several types of nitrogen-containing heteroaromatic compounds are also capable of producing carboxonium-centered dications (Table 3).45 Among the dications 108-113, all have been shown to react with weak nucleophiles such as benzene, deactivated arenes, and even saturated hydrocarbons. Moreover, their reactivities greatly exceed that of comparable monocationic electrophiles. In the case of dication 111, for example, it is shown that it will condense with benzene in a hydroxyalkylative conversion (eq 36).45d... 

Peng, X., Fukui, N., Mizuta, M. and Suzuki, H. Nitration of moderately deactivated arenes with nitrogen dioxide and molecular oxygen under neutral conditions. Zeolite-induced enhancement of regioselectivity and reversal of isomer ratios, Org. Biomol. Chem., 2003, 1, 2326-2335. 

Most known iodonium salts of this category have one phenyl and one aryl group. Various hypervalent iodine precursors can be used as effective electrophiles, notably the combination of (diacetoxyiodo)benzene with triflic acid. The reagent is formed in situ and is suitable for a range of activated to weakly deactivated arenes. The reactions proceed at room temperature and in some cases, e.g. with anisole, only the p-isomer was produced. Strongly deactivated arenes such as nitrobenzene did not react. 

Another approach for the preparation of either symmetrical or unsymmetrical iodonium salts used organolithium or organomercury compounds and (dichloroiodo)arenes [12]. The problem of the formation of unwanted isomers during reactions involving aromatic electrophilic substitution may also be overcome by the condensation of iodosylarenes with iodylarenes [12]. Several iodonium triflates were prepared in high yield from activated or mildly deactivated arenes with iodosylbenzene and triflic anhydride or triflic acid [13,14] or sulphur trioxide [15]. Some of these compounds are shown in Table 8.2. 

Aromatic bromination.1 BrF readily undergoes both ionic and radical reactions with arenes, but addition of C2H5OH suppresses radical reaction and permits electrophilic bromination. Simple arenes give mono- and dibromo derivatives. BrF is more useful for bromination of deactivated arenes as shown. 

Iodination of arenes2 Iodination of arenes can be effected by reaction with HgO HBF4 in the presence of iodine. The orientation conforms to that observed in electrophilic aromatic substitution except that ortho-attack is favored over para-attack in activated arenes. The method is particularly useful for meta-iodination of deactivated arenes (99% selectivity). 

The direct mercuration of arenes is widely used for the synthesis of arylmercurials. The reaction is particularly efficient for activated arenes (such as phenols, anilines, and aryl ethers), while deactivated arenes require the use of stronger electrophiles and higher reaction temperatures. A recent example of the latter is the mercuration of terephthaldehyde reported by Vicente (equation 6) ... 

Nitration. Regioselective mononitration (but no further) of moderately deactivated arenes is accomplished with urea nitrate or nitrourea, despite their use in excess. 

Deactivated arenes are brominated with NBS-CF3C00H-H2S04. ... 

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