Haloarenes nucleophilic substitution

C—Cl bond acquires a partial double bond character due to resonance. As a result, the bond cleavage in haloarene Is difficult than haloalkane and therefore, they are less reactive towards nucleophilic substitution reaction. 

Halogen exchange between an aryl carbanion and a haloarene is well established and occurs by nucleophilic substitution on the halogen substituent [154]. This pro-... 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

The methods of synthesis of diaryl and aryl alkyl selenides have been recently reviewed.215 4-Nitro-phenyl methyl selenide was obtained in 93% yield from the reaction of 4-chloronitrobenzene in DMF with a suspension of MeSeLi in THF, prepared from powdered Se and MeLi.216 Other mixed RSeAr selenides were synthesized via alkylation with RI of ArSe resulting from the nucleophilic substitution of unactivated haloarenes ArCl with MeSeLi in DMF at 120 C, followed by MeSe -induced demethyl-ation.217... 

Ionic liquids can be used as replacements for many volatile conventional solvents in chemical processes see Table A-14 in the Appendix. Because of their extraordinary properties, room temperature ionic liquids have already found application as solvents for many synthetic and catalytic reactions, for example nucleophilic substitution reactions [899], Diels-Alder cycloaddition reactions [900, 901], Friedel-Crafts alkylation and acylation reactions [902, 903], as well as palladium-catalyzed Heck vinylations of haloarenes [904]. They are also solvents of choice for homogeneous transition metal complex catalyzed hydrogenation, isomerization, and hydroformylation [905], as well as dimerization and oligomerization reactions of alkenes [906, 907]. The ions of liquid salts are often poorly coordinating, which prevents deactivation of the catalysts. 

Trifluoromethyl trimethylsilyl sulfide. This reagent is obtained by reaction of MCjSil with CFjSag in pyridine at 80°. It is a source of trifluoromethanethiolate for nucleophilic substitution of activated haloarenes. 

The mechanism of the amines or alcohols arylation catalyzed by nickel(II) complexes has not been elucidated until now (refs. 7, 17), even though the arylation of nucleophiles catalyzed by nickel(0) complexes is better understood. In this last case it is generally admitted that the reaction proceeds by an oxidative addition step, followed by a nucleophilic substitution, and then a reductive elimination of the arylation product (Scheme 4). According to the work of Kochi (ref. 18), the oxidative addition of the haloarene on a nickel(O) complex takes place through a monoelectronic transfer from the metal to the aryl halide with simultaneous formation of a nickel(I) intermediate, the actual catalyst of the reaction (ref. 6). 

Complexes of haloarenes undergo nucleophilic substitution of the halogen by stabilized carbanions to generate the substituted arene complex. - This reaction occurs with nucleophiles that add reversibly to the arene ring because the kinetically preferred site of attack is ortho and meta to the halogen. As noted above, extrusion of the halogen and a productive substitution reaction occurs upon addition to the less-favored carbon located ipso to the halogen (Equation 11.53). 

Aryl exchange occurs before transmetallation. Thus, the transmetal-lation rate constant which is low for steric and electronic reasons results in increasing the coupling product of phosphine-bound aryls (Eq. 51). Transmetallation is slowed down when electron-rich haloarenes and weak bases are used and accelerated with electron-deficient haloarenes because the transmetallation shown in Eqs. 16 and 17 involves nucleophilic substitution of Pd-X. The reported equilibrium ratio of 3/5 is 4/96 at 60 °C when Ar is p-methoxyphenyl. Thus, it is quite reasonable that the reaction accompanies a large amount of 6 when the rate constant of transmetallation ifej is lower than ky A strong base, polar solvent, and a sterically less hindered bidentate ligand, such as dppf, increase k. The formation of yields of 9 in p-iodoanisole higher than the bromo derivative... 

Similarly, PTC nucleophilic substitution with inorganic anions can be realized with activated haloarenes. These reactions proceed via addition-elimination mechanism. Some examples are given below (eqs. 147 and 148). 

Nucleophilic aromatic substitution reactions of haloarenes complexed to transition metal moieties with oxygen-, sulfin-, and nitrogen-containing nucleophiles allows for the synthesis of a wide variety of aryl ethers, thioethers, and amines. These metal-mediated reactions proceed under very mild conditions and allow for the incorporation of a number of different functional groups. Nucleophilic substitution reactions of chloroarenes complexed to the cyclopentadienyliron moiety have been the focus of many studies directed toward the design of functionalized organic monomers. ... 

The "radical anion" or S/ l mode offers a coherent explanation for so-called "direct" nucleophilic substitutions in the absence of activating electron-acceptors. It accounts also for other organometallic condensation reactions that neither obey an Sat2 nor an addition/elimination mechanism. In this category falls the condensation of haloarenes with second and higher row elements. As typical examples may be quoted the... 

Nucleophilic substitution of haloarenes is difficult, and poor reactions are obtained unless the arene bears a group able to accept electrons by resonance. 

Photonucleophilic aromatic substitution reactions of phenyl selenide and telluride with haloarenes have also been proven to involve the S jlAr mechanism, with the formation of anion radical intermediates. Another photonucleophihc substitution, cyanomethylation, proves the presence of radical cations in the reaction mechanism. Liu and Weiss have reported that hydroxy and cyano substitution competes with photo substitution of fluorinated anisoles in aqueous solutions, where cation and anion radical intermediates have been shown to be the key factors for the nucleophilic substitution type. Rossi et al. have proposed the S j lAr mechanism for photonucleophihc substitution of carbanions and naphthox-ides to halo anisoles and l-iodonaphthalene. > An anion radical intermediate photonucleophilic substitution mechanism has been shown for the reactions of triphenyl(methyl)stannyl anion with halo arenes in liquid ammonia. Trimethylstannyl anion has been found to be more reactive than triphenylstannyl anion in the photostimulated electron- transfer initiation step. 

Benzotriazoles, for example, are accessible from o-aminoaryl-substituted triazenes after a two-step reaction sequence a nucleophilic displacement followed by cleavage/heterocyclization.35 The nucleophilic halide displacement of activated haloarenes is an indispensable tool for the synthesis of highly substituted arenes. Fluoronitroarenes in particular have served as excellent precursors in this transformation. Thus, it was appealing to combine this SNAr reaction with the flexibility of diazonium chemistry. In this case, an immobilized fluoronitrophenyl triazene would be the equivalent of the Sanger reagent. 

Copper complexes of substituted haloarenes have been shown to be particularly prone to displacement of halide by nucleophiles. Most commonly, copper(n) species are involved, but in a few cases copper(i) has also been shown to be effective. This is not surprising in view of the facile inter-conversion of copper(i) and copper(n) in aerobic condi-... 

The thermolysis of iodonium salts in which their counteranion is a halide may be performed in the molten state or in solution the products are an iodoarene and a haloarene. The reaction which is a nucleophilic aromatic substitution is, however, not preparatively useful an exception was 3-indolyl phenyliodonium trifluoroace-tate which on heating with various chlorides and bromides in DMSO afforded variable mixtures of 2- and 3-haloindoles. By contrast, the jV-methyl and N-benzyl analogues gave only 2-chloro derivatives [58], Sometimes useful products may be obtained from the thermolysis of dibenziodolium or other heterocyclic salts, as exemplified in the preparation of l-iodo-2-(2-iodophenyl)naphthalene [59] ... 

In the S l reactions with nucleophiles of the types RS , PhS, PhSe", PhTe , Ph2As and Ph2Sb , fragmentation reactions of the radical anions of the substitution products are often observed. A review on the phenomenon of radical anion fragmentation in the course of aromatic S l reactions has appeared in 1982692. The mechanism of fragmentation was also very clearly described in a report on photostimulated reactions of haloarenes with benzeneselenate ions693. In the photostimulated reaction of />ara-iodoanisole (247) with benzeneselenate ions (248) not only the straightforward substitution product 249 was obtained, but also the symmetrical diphenyl selenide (250) and the di-(/ -anisyl) selenide (251) (equation 182). 

The reactivity of complexed haloarenes toward thiolates has been studied, and it has been reported that o-, m-, and p-dichlorobenzenetricarbonylchromium complexes 18a-c react with thiolates (RS R = Me, nBu, tBu Scheme 17, path i) under phase-transfer conditions or in DMSO to give 39 and 40a-c. The ortho- and para-complexes 18a and 18c undergo stepwise substitution of the two Cl atoms in a reaction sequence that can be easily controlled by the amount of added thiolate. The meta complex 18b shows a lower selectivity and gives a mixture of mono- and disubstituted products even in the presence of substoichiometric amounts of thiolate (Scheme 17) [22]. Similarly, LiCH(C02Et)CN and BuSH react with the o-dichlorobenzene complex 18a to give complex 39d and then disubstituted arene 40d, showing that this substitution can be performed with two different nucleophiles (Scheme 17) [23]. Phase-transfer catalysis has also been applied to fluoroarene-Cr(CO)3 complexes, which are more reactive toward thiolates than are the corresponding chloro derivatives [22]. 

RCO , an indifferent nucleophile in prohc solvents, enjoys a large rate enhancement, permitting rapid alkylation with haloalkanes in hexamethylphosphoric triamide [301, 302], When the Williamson ether synthesis is carried out in dimethyl sulfoxide [303], the yields are raised and the reaction time shortened. Displacements on unreactive haloarenes become possible [304] (conversion of bromobenzene to tert-butoxybenzene with tert-C UgO in dimethyl sulfoxide in 86% yield at room temperature). The fluoride ion, a notoriously poor nucleophile or base in protic solvents, reveals its hidden capabilities in dipolar non-HBD solvents and is a powerful nucleophile in substitution reactions on carbon [305],... 

Sonochemistry has been applied to acceleration of the Reformatsky reaction, Diels-Alder reactions, the arylation of active methylene compounds nucleophilic aromatic substitution of haloarenes, and to hydrostannation and tin hydride reduction. " Other sonochemical applications involve the reaction of benzyl chloride and nitrobenzene, a Sr I reaction in liquid ammonia at room temperature, and Knoevenagel condensation of aromatic aldehydes. lodination of aliphatic hydrocarbons can be accelerated, and oxyallyl cations have been prepared from ot,ot -diiodoketones using sonochemistry. Sonochemistry has been applied to the preparation of carbohydrate compounds.When sonochemistry is an important feature of a chemical reaction, this fact will be noted in the reactions presented in Chapters 10-19. 

The complexes generated by oxidative addition of haloarenes and haloalkenes to palladium(O) are electrophilic at the metal-substituted center, and can therefore react with carbon nucleophiles other than alkenes, especially with enolate and homoenolate ions to form new C—C bonds [176, 177]. 

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