Benzene nucleophilic reactions

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

If one limits the consideration to only that limited number of reactions which clearly belong to the category of nucleophilic aromatic substitutions presently under discussion, only a few experimental observations are pertinent. Bunnett and Bernasconi30 and Hart and Bourns40 have studied the deuterium solvent isotope effect and its dependence on hydroxide ion concentration for the reaction of 2,4-dinitrophenyl phenyl ether with piperidine in dioxan-water. In both studies it was found that the solvent isotope effect decreased with increasing concentration of hydroxide ion, and Hart and Bourns were able to estimate that fc 1/ for conversion of intermediate to product was approximately 1.8. Also, Pietra and Vitali41 have reported that in the reaction of piperidine with cyclohexyl 2,4-dinitrophenyl ether in benzene, the reaction becomes 1.5 times slower on substitution of the N-deuteriated amine at the highest amine concentration studied. 

Xanthobacter sp. strain Py2 may be grown with propene or propene oxide. On the basis of amino acid sequences, the monooxygenase that produces the epoxide was related to those that catalyzes the monooxygenation of benzene and toluene (Zhou et al. 1999). The metabolism of the epoxide is initiated by nucleophilic reaction with coenzyme M followed by dehydrogenation (Eigure 7.13a). There are alternative reactions, both of which are dependent on a pyridine nucleotide-disulfide oxidoreductase (Swaving et al. 1996 Nocek et al. 2002) ... 

Bromomethylhenzene or henzylhromide can he subjected to further nucleophilic reactions. Bromine can be replaced by a variety of nucleophiles by means of an Sn2 and SnI reaction, resulting in various monosubstituted benzenes. 

By contrast, measurement of pATR = 4.7 for the Fe(CO)3-cooordinated cyclo-hexadienyl cation 44 (Scheme 26) indicates a 107-fold more favorable equilibrium constant for carbocation formation than for the uncoordinated cation.197 However, a more dramatic effect of coordination is to render nucleophilic reaction with water more favorable than loss of a proton. A pXa = 9 can be estimated by computing the energy differences between coordinated and uncoordinated benzene and coordinated cyclohexadiene. This compares with the value of —24.5 for the uncoordinated cyclohexadienyl cation. The large difference must reflect the unfavorable effect of Fe(CO)3 coordination on benzene, an effect analogous to that found by Mayr for Fe (CO)3 coordination on the tropylium ion.196 As expected, both the coordinated cyclohexadienyl and tropylium ions are highly stereoselective toward exo attack by water. 

From other o-substituted benzenes. Standard reactions of aliphatic chemistry can be applied for example, chroman 102 can be prepared by ring closure of 101. 4-Quinolones result from the Camps reaction (103 104), and flavonone 106 is prepared by cyclization of 105. The nucleophile-induced cyclization of suitably substituted 0-alkynylanilines 107 provides a general synthetic approach to quinolines 108 (Scheme 66) . Similar cyclizations of o-alkynylphenols lead to the formation of coumarins . 

The nucleophilic reaction between two uncharged partners is strongly dependent on the polarity of the solvent (69CRVI), as exemplified by the reaction between 4-nitrofluorobenzene and piperidine (63MI1) which is — 10 times faster in dimethylsulfoxide (DMSO), DMF. or N-methylpyr-rolidone than in benzene and is furthermore base catalyzed by the piperidine (63M1I 64CB3277). As mentioned in Section 1II,B, polar solvents such as A-methylformamide, DMF, A-methylpyrrolidone or HMPA can also serve as reactants in special cases to transform nitrogen heterocycles... 

Oxygen-sulfur heteroatom exchange has been achieved with 3-methyl-benzene thiazole-2-thione in the presence of trifluoroacetic acid and with l-phenyl-5-mercaptotetrazole. Thiirane can be prepared from oxirane on a support impregnated with alkali metal salts, by decomposition of the dithiocarbon-ate formed with carbon disulfide. A macrocyclic ether, perhydrobenzo-18-crown-6, plays a role in the nucleophilic reaction of oxirane with KCNS, which leads to thiirane in good yield. ... 

Huonne in nitro derivatives of benzene shows a greater reactivity than chlorine in nucleophilic reactions (3). In view of this attention was paid to 1,3.5-trinuorotrinitrobenzcnc and its reaction with nucleophiles 31. 

In particular, called resonance polar effect [Taft, 1956] is defined for any benzene derivative where there is no direct conjugation between substituent and reactive it can be considered constant for a particular solvent, therefore expressing resonance interactions between substituent and skeletal group. 6r is usually referred to as the effective resonance constant and of hold for electrophilic and nucleophilic reaction series, respectively. 

Apart from the use of a set of benzene derivatives with a constant ortho substituent, another case where the ortho substituent can be employed is where the steric effect is likely to be small or where the ortho group can take up a conformation during reaction where it does not interact with the reaction centre. A good example of this is the nucleophilic reaction of phenolate ions with 4-nitrophenyl acetate (Figure 10) where phenolate ions with single ortho substituents fit the Bronsted line defined by the meta and para substituent points. 

There are significant lessons to be learnt from the chemistry of purines since their reactions exemplify the interplay of its constituent imidazole and pyrimidine rings, just as the properties of indole show modified pyrrole and modified benzene chemistry. Thus purines can undergo both electrophilic and nucleophilic attack at carbon in the live-membered ring and mainly nucleophilic reactions at carbon in the six-membered ring. 

In a so-called vicarious nucleophilic substitution of hydrogen,75 2,3-diphenylpyrido[2,3-6]-pyrazine is alkylated in the 8-position by [(chloromethyl)sulfonyl]benzene. This reaction proceeds by addition of the carbanion to the electron-deficient ring position of a nitroarene or electrophilic heteroaromatic system, followed by base-induced -elimination of the corresponding hydrogen halide.76,77 As with quinoxalines and naphthyridines, the reaction with pyrido[2,3-6]pyrazines also affords products bisannulated at the pyrazine or the pyridine moiety, depending on the kind of 2/3-substitution (cf. Section 7.2.3.1.2.2.2.). 

From the calculations it is concluded that nucleophiles add favourably at position 2. This attack should occur more facile than in benzene. The reaction at the peripheral sulfur atom is predicted to be competitive with the one at position 2. Both models mentioned explain qualitatively the experimental results. 

Nucleophilic reactions take place on the hetero ring of isoquinoline, preferably in the 1-position. For instance, the Chichibabin amination with NaNH2 in liquid ammonia yields 1-aminoisoquinoline 5. The Ziegler reaction with w-butyllithium furnishes the 1-substituted product 7 as with quinoline, benzene ring annulation stabilizes the primary addition product 6 (1,2-dihydroisoquinoline), which can be isolated and dehydrogenated to 7 by nitro compoxmds ... 

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