Substitution, SNAr, activating

SNAr substitutions of activated aromatic halides, especially aromatic fluorides, provide useful means for the construction of aromatic diethers or amines. Primary and secondary amines react with l, 2-dihalo-4,5-dinitrobenzene to give nitro group substitution at room temperature. The halogen substituents on the ring remain unsubstituted and can be used in further transformation (Eq. 9.5).8... 

Secondary steric effects could become significant in aromatic nucleophilic substitution in activated halogenoben-zenes. This can be ascribed to steric inhibition of resonance. In contrast, secondary steric effects are not important in SNAr reactions of thiophene derivatives this is due to the geometry of five-membered ring derivatives, which strongly lowers the steric interactions between the substituents on the thiophene ring. This has been reconfirmed by kinetic data in methanol on SNAr reactions of the two pairs of substrates 210 and 211 with different nucleophiles (piperidine and sodium benzenethiolate) <1997J(P2)309>. 

Furthermore, the stronger C-F bonds, compared with other C-halogen bonds such as the C-Cl, are the actual thermodynamic driving force for Halex reactions towards the fluoroaromatics [57]. The Halex reaction is a nucleophilic aromatic substitution (SNAr) in which chlorine atoms activated by an electron-withdrawing group are displaced by fluorine upon reaction with a metal fluoride under polar aprotic conditions [58]. 

We have recently reported ( ) several synthetic studies of weak nucleophile SnAr reactions. In the latter cases (26f-1), new synthetic methodology was reported for the direct introduction of fluoroalkoxy groups into a variety of aromatic systems. These reports represent synthetically useful procedures for obtaining some otherwise inaccessible fluoroalkoxy materials but, unfortunately, they require the use of a dipolar, aprotic solvent (usually hexamethylphosphoramide, HMPA) and, in some cases, elevated temperatures. However, because of their diverse and important applications ( ), the syntheses of these and other organofluoro compounds continue to be of interest. For example, two recent reports of useful fluoroalkoxy materials include the insecticide activity exhibited by fluoroalkoxy substituted 1,3,4-oxadiazoles... 

While the greatest percentage of PTC-aided anionic substitutions involve non-aromatic systems (7-10), a number of liquid-liquid and solid-liquid, PTC-aided SnAr reactions have been reported (32-38). These reports involve a variety of substrates [unactivated (32,33), slightly activated (M), activated (35-37), and transition metal complexed 32,38)1, nucleophiles OMe (32,38), CN ( ), SR (34) SCN (36), SO (36), OR (37)] and PTCs... 

Jawdosiuk et al.220 have treated 4-chloro- and 4-nitropyridine N-oxides (145) with substituted phenylacetonitrile. This is in agreement with the well-known activating effect of N-oxides toward SNAr reactions the results show that nitro is a better leaving group than chloro. 

Nucleophilic attack is faster at unsubstituted ring positions than at similarly activated but substituted ring positions.8-15-43 5 Since the addition is in most cases reversible, the opportunity exists for competing reactions. Indeed an extremely varied spectrum of reactivities is found in these systems, depending on reactants and reaction conditions. Examples are known of competing SNAr and cine substitution,46 NAr and tele substitution,47 SnAt and cine and tele substitution (equation l),5 SsAr and VNS,16 and SnAt and Sn(ANRORC).48... 

The isolation of the first halobenzene complex, (q6-chlorobenzene)tricarbonylchromium(0), allowed a test for a direct analog of classical SNAr reactivity.15 The activating effect of the Cr(CO>3 unit was found to be comparable to a single p-nitro substituent in reaction with methoxide in methanol and the substituted arene ligand was detached with mild oxidation (equation 2). 

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. 

Metal-based nucleophiles may react with activated haloarenechromium complexes leading to substitution of the halides. The reaction of Collmarfs reagent Na2[Fe(CO)4] with chloro-arenetricarbonylchromium complexes in THF/N-methylpyrrolidinone produces the yellow anionic dinuclear complexes 91a in 45 % yield (Scheme 40) as a result of an ipso SNAr [64]. Spectroscopic data suggest that complex 91a adopts the rj6 structure as opposed to the alternative //5 -cyclohexadieny 1 carbene structure 92. Similarly, it has been reported by the same group that the potassium salt of [CpFe(CO)2] participates in ipso nucleophilic attack on chloroarenechromium substrates, producing dinuclear complexes 91b in 92 % yield (Scheme 40) [65]. 

Electrophihc substitution reactions take place at the ring-C-atoms, preferentially on those of the more activated benzene moiety. The relative reactivities of the individual quinoline positions were determined for the acid-catalyzed H-D-exchange with D2SO4 this SnAr process proceeds via the quinoUrtium ion and with the positional selectivity C-8 > C-5/C-6 > C-7 > C-3 [156],... 

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