SUBSTITUTION OF ARYL HALIDES

For model reactions, we chose the aromatic substitution of aryl halides with nucleophiles such as phenolates or amines. The reaction parameters particularly focused upon were reaction time, selectivity, work-up procedure, and overall processing time. 

ETHYL 4-METHYL-E-4,8-NON-ADIENOATE, 53, 116 Styrene, reaction with carbe-thoxycarbene, 50, 94 Suberoyl chloride, 54, 88 SUBSTITUTION OF ARYL HALIDES WITH COPPER(I) ACETYLIDES ... 

SUBSTITUTION OF ARYL HALIDES WITH COPPER(I) ACETYLIDES 2-PHENYLFURO[3,2- ]PYRIDINE... 

In the copper catalyzed aromatic nucleophilic substitution of aryl halides bromoindole derivatives were converted to the appropriate cyanoindoles. Both 5-bromoindole and its 7V-tosyl derivative gave excellent yields, when a substoichiometric amount potassium iodide was added to the reaction mixture (6.80.), Pyrazole and benzothiophene showed a similar reactivity. The role of the added iodide is to activate the aromatic system through a bromine-iodine exchange.111... 

Photoinduced nucleophilic substitution of aryl halides with potassium thioacetate. A one-pot approach to aryl methyl and diaryl sulfides. European Journal of Organic Chemistry, 2210-2214. 

Nucleophilic substitution of aryl halides is a facile route for activated systems, for instance in the displacement of CT from 2,4-dinitrochlorobenzene with Nal358. The exchange of o-iodohippuric acid has been rationalized by suggesting the stabilization of the intermediate complex by delocalization of the negative charge359 (equation 174). 

It has been proposed that copper-mediated substitutions of aryl halides proceed by formation of intermediate Cu(III) species, which reductively eliminate to the cross-coupling products (equation 52)74. 

A typical reaction is the photostimulated substitution of aryl halides by ketone [121-131] (and much less efficiently aldehyde [124]) enolate anions (Scheme 5), both inter- [121-128] and intramolecularly [129-131]. The SRN1 reaction with o-bromoacetophenones is a useful method for the construction of an aromatic ring (Scheme 24) [132-133], with o-halophenylalkyl ketones for macrocycles (Scheme 25) [134], with o-haloanilines for indoles [123], with o-halobenzylamines for isoquinolines [135], and several other heterocyclic syntheses are possible [136]. 

The best known PET bond cleavage reaction involves the substitution of aryl halides by the S l mechanism. This mechanism was first recognized by Bunnett and Rossi in 1970 [55]. The SRN1 mechanism [56,57] requires one-electron reduction of an aryl halide to initiate the substitution reaction. The anion-radical undergoes... 

The electrophilic aromatic substitution of aryl halides takes place less readily than with benzene (electron-withdrawing effect), but occurs at the ortho and para positions (the lone pairs on the halogen assist in delocalizing the positive charge in the intermediate). Further chlorination of chlorobenzene, in the presence of aluminium or iron trichlorides, gives 1,4-dichlorobenzene and some 1,2-dichlorobenzene. Nitration normally occurs to give the 2- and 4-nitro- and 2,4-dinitrochlorobenzenes (Scheme 4.13). 

Bacon, R. G. R., Karim, A. Copper-catalyzed substitution of aryl halides by potassium phthalimide an extension of the Gabriel reaction. J. 

Trifluoromethylarenes. - The substitution of aryl halides to give ArCFj by heating with ClCF2COOMe, KF, and Cul in DMF involves insertion of difluorocar-bene into C-Cu bonds. 

In the mid-1970s it was discovered that phosphine-Ni complexes (e.g., (Ph3P)2NiCl2) catalyzed the substitution of aryl halides with Grignard reagents at room temperature. The Ni catalysts were mostly phosphine complexes of NiCla. Alkyl (1°, 2°, or 3°), aryl, or alkenyl Grignard reagents could be used. 

Palladium-catalyzed substitutions of aryl halides have emerged as a powerful tool for making carbon-carbon bonds. The most widely used of these arylations leads to substitution of a vinylic hydrogen of an alkene by an aryl group and is called the Heck reaction after Richard F. Heck (University of Delaware) who pioneered its development. 

Once again, the nickel-catalysed reactions are far more sensitive to the steric encumbrances, than the palladium-catalysed analogues. Aryl triflates and related sulfonates can serve as the electrophilic reactants in the Kharasch reactions in the presence of an equimolar amount of lithium bromide. The latter additive is a reagent for triflate-bromide exchange, which became a very fast reaction under the Kharasch reaction conditions, since the nickel and palladium-catalysed nucleophilic substitutions of aryl halides and sulfonates are well established reactions, see Chapter 3. In this manner, 2-biphenyl triflate (135) was reacted with 4-tolylmagnesium bromide (136) to give 2-(4-tolyl)biphenyl (137) with a 93% yield [40], respectively. Scheme 8. 

The use of transition-metal catalysts in the substitution of aryl halides by amines has been reviewed. There has also been a summary of the use of palladium catalysts in the reaction of aryl and heteroaryl halides with primary and secondary amines. It has been shown that the amination of aryl sulfamates by aliphatic amines may be achieved using a nickel catalyst with an A-heterocyclic carbene ligand. Suitable ligands for nickel and palladium in the catalysed amination reactions of aryl sulfamates and imidazolylsulfonates have been identified. " The palladium-catalysed reaction of aryl nonafluorobutanesulfonates with primary sulfonamides may yield substituted products such as (22). Kinetic data suggest that reductive elimination from the palladium intermediate is likely to be rate limiting. A-Arylmethanesulfonamides may also be formed from aryl bromides and chlorides using a palladium catalyst... 

Owing to the extreme difBculty of nucleophilic substitution of aryl halides, hydrolysis will not likely occur in natural waters. Nitro compounds also resist hydrolytic scission. Thus, in general, hydrolysis under ambient environmental conditions is highly improbable. 

As noted in Chapter 9, conventional nucleophilic substitution reactions of the type described for aliphatic compounds don t occur at sp hybrid carbon atoms. The formation of aryl cations is disfavored because they are unstable, and attack from the backside of the C-halogen bond is rendered impossible by the ring structure. So the substitution of aryl halides is much more difficult, and the mechanism of the S).j2Ar reaction is quite different, involving addition followed by elimination—a two-step process. For example, although substitution of chlorobenzene by hydroxyl ion is possible, conditions are harsh (350 °C, high pressure), and even then, yields are low. The reaction (Figure 13.13) probably involves a benzyne intermediate (see Sections 10.9 and 13.6). 

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