Nucleophiles, reaction with halobenzenes

Figure 8-5. Reactions of halobenzene derivatives with nucleophiles, a) Unactivated compounds are extremely inert and only react by mechanisms that involve the formation of benzynes. b) The presence of the electron-withdrawing nitro group, which can stabilise an anionic intermediate by the delocalisation of the charge onto the electronegative oxygen atoms, allows facile nucleophilic substitutions.

In the reaction with nucleophiles, halobenzenes with electron-withdrawing substituents such as nitro group in ortho or para (or both) positions activate the halogens for nucleophilic displacement. Which halogen is replaced more easily, chlorine or fluorine Explain why. 

Two suitably positioned nitro groups make the halogen-bearing carbon atom in 2,4-dinitro-halobenzenes a favored point of reaction for nucleophilic substitution reactions. Thus, 2,4-dinitrophenyl hydrazine is produced from the reaction of 2,4-dinitrochlorobenzene with hydrazine ... 

The reaction of halobenzenes with a strong base (e.g. NaNH2 in NH3) can lead to the elimination of HX and the formation of benzyne (in a synperiplanar elimination reaction). The new Jt-bond that is formed (by the overlap of two sp2-orbitals outside the ring) is very weak, and benzyne can react with nucleophiles or take part (as the dienophile) in Diels-Alder reactions (see Section 6.2.2.11). As benzyne is extremely... 

While we have seen that ordinary halobenzenes are resilient to reaction with hydroxide, they undergo such nucleophilic displacements in the presence of Pd salts and added phosphine ligands PR3. 

Solvent-free SNAr reactions under solid-liquid PTC conditions were realized by using methoxide or phenoxide as nucleophiles. The main results, and comparison with those from classical heating, are indicated in Tab. 5.24 for activated (e.g. 4-nitro-halobenzenes) or nonactivated (e.g. a-naphthyl halides) substrates [74]. 

Nucleophilic astatination of halobenzenes CgHjX (X = Cl, Br, I) in homogeneous mixtures with -C4H9NH2, (C2H5)2NH, and (C2Hj>3N at 210° C has led to the formation of astatobenzene with radiochemical yields of 75-90% 143, 144). A two-step process has been postulated [Eqs. (10) and (11)], with the latter reaction [Eq. (11)] as the ratedetermining step ... 

The reactivities of aryl halides, such as the halobenzenes, are exceedingly low toward nucleophilic reagents that normally effect displacements with alkyl halides and activated aryl halides. Substitutions do occur under forcing conditions of either high temperatures or very strong bases. For example, chlorobenzene reacts with sodium hydroxide solution at temperatures around 340° and this reaction was once an important commercial process for the production of benzenol (phenol) ... 

Protic solvents (other than ammonia) are generally unsuitable on account of their high acidity relative to that of most nucleophiles used in SrnI reactions. Water was found to be unsuitable, even with water-soluble substrates and weakly basic nucleophiles.46 The reported reaction of halobenzenes with PhO in 50% aqueous Bu OH, catalyzed by sodium amlagam,51 was shown to be unreproducible.52 Methanol was used as solvent in an unusual reaction, believed to be occurring by the Srn 1 mechanism and catalyzed by MeO" at 147 °C, in which PhS replaces the bromine in 3-bromoisoquinoline.53 Other protic solvents have been reported to give acceptable yields in SrnI reactions, but on the whole these involve substrates which give good yields in other solvents as well. 

Nucleophilic substitution of unactivated benzene derivatives occurs by a mechanism different from the addition-elimination we saw with the nitro-substituted halobenzenes. A clue to the mechanism is provided by the reaction of p-bromotol ucnc with sodium amide. The products are a 50 50 mixture of m- andp-toluidine. 

Similar substitutions are obtained with the carbanions of esters [129, 131], /V,7V-disubstituted amides [137-138] and nitriles [139-140]. The anion of cyclohexylideneacetonitrile reacts with p-bromoanisole exclusively at the y position (Scheme 26) [141]. The ambient anions of phenols and anilines react as carbon nucleophiles, as observed in the reactions of halobenzenes with 2-naphthylamine [142], 2-naphthol [143] and various phenols (Scheme 27) [144-145],... 

Intermolecular Nucleophilic Substitution with Heteroatom Nucleophiles. A patent issued in 1965 claims substitution for fluoride on fluorobenzene-Cr(CO)3 in dimethyl sulfoxide (DMSO) by a long list of nucleophiles including alkoxides (from simple alcohols, cholesterol, ethylene glycol, pinacol, and dihydroxyacetone), carboxylates, amines, and carbanions (from triphenyhnethane, indene, cyclohexanone, acetone, cyclopentadiene, phenylacetylene, acetic acid, and propiolic acid). In the reaction of methoxide with halobenzene-Cr(CO)3, the fluorobenzene complex is ca. 2000 times more reactive than the chlorobenzene complex. The difference is taken as evidence for a rate-limiting attack on the arene ligand followed by fast loss of halide the concentration of the cyclohexadienyl anion complex does not build up. In the reaction of fluorobenzene-Cr(CO)3 with amine nucleophiles, the coordinated aniline product appears rapidly at 25 °C, and a carefiil mechanistic study suggests that the loss of halide is now rate limiting. 

Nucleophilic substitution reactions of unsaturated compounds containing the G=G double bond are well known and are distinguished by the relative location of the double bond and leaving group. Rappoport has recently reviewed the wide and complex nature of nucleophilic vinylic substitutions. The susceptibility of simple vinyl compounds to nucleophilic attack is low and comparable to unactivated halobenzenes. As is the case with aromatic compounds, however, vinylic substrates may be activated by electron-withdrawing substituents conjugated with the reaction centre. 

The majority of reported reactions of aryl and heteroaryl substrates with organocopper reagents are examples of Stephens-Castro coupling or the more recent catalytic version of that reaction. The reaction has found recent application in syntheses of C-(6)-substituted pterins and pteridines, substituted pyridines, and the antitumor antibiotic fredericamycin A," to name a few. Aryl iodide can be che-mospecifically displaced in the presence of bromide," and 2,5-dibromopyridine is regioselectively substituted at the 2-position. Substitution of halobenzenes by propargyl alcohol, followed by oxidative cleavage, provides a convenient route to terminal arylalkynes. " Fused heterocycles are formed in reactions of aryl halides bearing nucleophilic ortho substituents. - "... 

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