Nuclear Substitution

The possibility to functionalize aromatic compounds by electrochemical methods is of great interest to chemical industry. Therefore, considerable efforts were made to develop the electrochemical oxidation of benzene to p-benzoquinone to the industrial scale thus forming a basis for a new hydroquinone process. The electrochemical oxidation of benzene in aqueous emulsions containing sulfuric acid using divided cells and Pb02 anodes formsp-benzoquinone. The product can then be reduced cathodically to yield hydroquinone in a paired synthesis. 

Conversion of benzene 10°/ Selectivity for hydroquinone 79% Current efficiency 38% 

Hoechst113-114) took a different approach to the synthesis of / -benzoquinone. By oxidation of benzene in methanol solution in the presence of tetraalkylammonium fluorides as conductive salts p-benzoquinone tetramethyl ketal is formed. This can be converted to p-benzoquinone in a simple procedure while methanol can be recycled. 

The brat results have been obtained at glassy carbon anodes U5). The primary intermediate in the synthesis is anisole. Using anisole as starting material instead of benzene the ketal can be obtained in better selectivitira (up to 85 %)116). 

All three types of reactions can also be used for the production of substituted quinones and hydroquinones. For example, BASF has developed two laboratory processes for the synthesis of trimethyl-p-benzoquinone and trimethylhydroquinone. The latter is required for the synthesis of vitamin E. 

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A white solid, m.p. 178 C. Primarily of interest as a brominaling agent which will replace activated hydrogen atoms in benzylic or allylic positions, and also those on a carbon atom a to a carbonyl group. Activating influences can produce nuclear substitution in a benzene ring and certain heterocyclic compounds also used in the oxidation of secondary alcohols to ketones. 

Fischer-Hepp rearrangement The nitros-amines of aromatic secondary amines when treated with hydrochloric acid give nuclear substituted nitrosoamines. Among the benzene derivatives, if the para position is free the -NO group displaces the hydrogen atom there in naphthalene derivatives it enters the 1-position ... 

Aniline undergoes very ready nuclear substitution by bromine even in the cold, the bromine atoms entering the two ortho positions and the para position with the formation of symmetric or 2,4.6-tribromoaniline. The presence... 

This rapid formation of the crystalline quinoxaline derivative can therefore be used to identify 1,2-diketones conversely, a nuclear-substituted o-phenyl-enediamine can be identified by the quinoxaline derivative which it forms with a known 1,2-diketone such as benzil. 

The success of the Bart reaction when applied to nuclear- substituted anilines is often much affected by the pH of the reaction-mixture. Furthermore, the yields obtained from some m-substituted anilines, which under the normal conditions are usually low, arc considerably increased by the modifications introduced by Scheller, and by Doak, in which the diazotisation is carried out in ethanolic solution followed by reaction with arsenic trichloride in the presence of a cuprous chloride or bromide catalyst. 

Phenol, 0-, m- and p-cresol, catechol, resorcinol, hydro-quinone (and other nuclear substituted phenols), 1 - and 2-naphthoi... 

Acetone ethyl methyl ketone diethyl ketone acetophenone, ben-zophenone (and their nuclear-substituted derivatives). Cyclohexanone. 

B) SULPHONIC ACIDS. Aliphatic sulphonic acids are rarely encountered, for they are very soluble in water, and many are deliquescent. The aromatic sulphonic acids, although less uncommon, are encountered most frequently as their derivatives e.g.t the sulphonamides, pp. 247, 251), or as nuclear-substituted acids (e.g., sulphanilic acid, p. 384). 

Methyl iodide ethyl bromide ethyl iodide, higher alkyl halides, chloroform, iodoform, carbon tetrachloride, chlorobenzene, bromobenzene, iodobenzene, benzyl chloride (and nuclear substituted derivatives)... 

Thus good yields (> 60 per cent) are obtained with aniline and methyl, ethyl, n-propyl and n-butyl phosphates with a- and P-naphthylamine and methyl or ethyl phosphate nuclear substituted anilines and methyl or ethyl phosphate. 

The chlorination of toluene in the absence of catalysts that promote nuclear substitution occurs preferentially in the side chain. The reaction is promoted by free-radical initiators such as ultraviolet light or peroxides. Chlorination takes place in a stepwise manner and can be controlled to give good yields of the intermediate chlorination products. Small amounts of sequestering agents are sometimes used to remove trace amounts of heavy-metal ions that cause ring chlorination. 

Although resorcinol [108-46-3], C H O, a dihydric phenol, is a comparatively weak bactericide, a nuclear-substituted alkyl derivative, -hexylresorcinol [136-77-6], has a phenol coefficient of 45, and has had considerable use as a topical antiseptic. 

Halogenomethyl, hydroxymethyl and aminomethyl groups readily undergo displacement reactions with nucleophilic reagents. Both side-chain and nuclear substitution products have been obtained (Scheme 57). These two possibilities are exemplified by the reaction of furfuryl chloride with sodium cyanide (Scheme 58). 

The nuclear substituted methyl styrenes have been the subject of much study and of these poly(vinyl toluene) (i.e. polymers of m- and /7-methylstyrenes) has found use in surface coatings. The Vicat softening point of some nuclear substituted methyl styrenes in given in Table 16.8. 

Polymers have been prepared from nuclear substituted di-(4-hydroxyphenyl)-alkanes, of which the halogenated materials have been of particular interest. The symmetrical tetrachlorobis-phenol A yields a polymer with a glass transition temperature of 180°C and melting range of 250-260°C but soluble in a variety of solvents. 

If chlorine and bromine are allowed to act upon an aromatic hydrocarbon like toluene, which has a side-chain, substitution may occur in the nucleus or the side-chain, according to the conditions. Generally speaking, in the cold and in presence of a halogen carrier, nuclear substitution occurs, Irut at a high temperatuie the halogen passes into the side-chain (see Piep. 

Probably the most important development of the past decade was the introduction by Brown and co-workers of a set of substituent constants,ct+, derived from the solvolysis of cumyl chlorides and presumably applicable to reaction series in which a delocalization of a positive charge from the reaction site into the aromatic nucleus is important in the transition state or, in other words, where the importance of resonance structures placing a positive charge on the substituent - -M effect) changes substantially between the initial and transition (or final) states. These ct+-values have found wide application, not only in the particular side-chain reactions for which they were designed, but equally in electrophilic nuclear substitution reactions. Although such a scale was first proposed by Pearson et al. under the label of and by Deno et Brown s systematic work made the scale definitive. 

A more quantitative formulation of the varying resonance effects in electrophilic nuclear substitution reactions has been suggested by Tsuno, who has proposed to use Eq. (2), where Aa+ is a resonance exaltation term, and r is a susceptibility constant. 

The bromination of 5,8-dimethoxyquinoxaline in methanol gives a mixture of 6-bromo and 6,7-dibromo compounds/ Treatment of 2-methylquinoxaline with bromine in acetic acid yields a mixture of 27% of 2 bromomethyl- and 37% of 2-dibromomethyl-quinoxaline." Thus in the absence of powerfully activating groups, side-chain rather than nuclear substitution takes place. 

Treatment of this with elemental iodine affords the nuclearly substituted iodo derivative (87). Removal of the benzyl ether by reduction leads to iodothiouracil (88). ... 

That reaction rates are barely affected by the nuclear substitution ill-accords with the hydride abstraction mechanism. However, nuclear substitution affects both the ionisation of the alcohol as well as the oxidation step. The value of k IkT agrees well with that of 55.5 calculated from kujk,) by means of the Swain relationship, i.e. kujkpy- = k lkr. 

Chlorine-substituted quinones, and especially chloranil (i.e., tetrachloro-quinone), are predominantly transfer agents rather than inhibitors. Nuclear substitution as in the first step of reaction (55) may be involved with subsequent transfer of a chlorine atom to a monomer molecule. ... 

This procedure, with minor changes, may be applied to various nuclear-substituted phenacyl chlorides. The yields vary from 74 to 92%.2-3... 

In contrast, triphenylphosphine displaces bromide smoothly and the Wittig reaction then possible provides the recommended synthesis of 2-nitro-5-vinylfuran as sketched in scheme 35, B.192 Halomethylfurans and cyanide ion give nuclear substitution, as has long been known (Scheme 35, C). Nuclear substitutions occur for 2,5-bis(chloromethyl)furan,193 but are less... 

Another series of nuclear substitution reactions of kojic acid might be represented as the addition of kojic acid to reactive multiple bonds, follow-... 

In most of these nuclear substitution reactions, kojic acid did indeed react as a phenol. An exception was the reaction with acrylonitrile, as noted by Woods.97 Phenols usually form cyanoethy ethers under similar conditions, but the reaction of acrylonitrile with ketones leads to substitution of the a-hydrogen atom.100 This consideration points to a predominance of the diketo form of the kojate anion (LXIV) in these reactions. There are many good reasons for believing that, in the formation of all these derivatives, substitution actually takes place at C6 it should, however, be pointed out that this assumption still lacks confirmation by synthesis or by appropriate degradation studies. The nuclear mono-substitution products of kojic acid are listed in Table IV, and their functional derivatives in Tables V and VI. 

Anisole under the same conditions gives only -methoxyacetophenone, even though the acetyl cation undoubtedly reacts faster with the methoxy group than with the benzene ring. Since no stabilizing car-bonium ion is split off the former reaction remains reversible and ineffective, while the nuclear substitution is pushed to completion by the removal of a proton. 

The effect of a substituent on the aromatic substitution reaction is similar to its effect on electrophilic side chain reactions, but not precisely parallel. Thus the Hammett relationship using the usual sigma or substituent constants gives considerable scatter when applied to aromatic substitution. The scatter is probably due to an increased importance of resonance effects in the nuclear substitution reaction as compared with the side chain reactions. 

Benzylsilanes are also oxidized under similar conditions with selective cleavage of the C Si bond (Scheme 4) [24,25], Nucleophiles are introduced onto the benzylic carbon exclusively. Nuclear substitution products are not formed. The high chemoselectivity observed for the reaction of p-(trimethylsilyl)benzyltrimethylsilane is interesting. Only the benzyl C-Si bond is cleaved without affecting the aromatic C-Si bond. 

The nitrosonium cation can serve effectively either as an oxidant or as an electrophile towards different aromatic substrates. Thus the electron-rich polynuclear arenes suffer electron transfer with NO+BF to afford stable arene cation radicals (Bandlish and Shine, 1977 Musker et al., 1978). Other activated aromatic compounds such as phenols, anilines and indoles undergo nuclear substitution with nitrosonium species that are usually generated in situ from the treatment of nitrites with acid. It is less well known, but nonetheless experimentally established (Hunziker et al., 1971 Brownstein et al., 1984), that NO+ forms intensely coloured charge-transfer complexes with a wide variety of common arenes (30). For example, benzene, toluene,... 

Cram et a .15>46> have investigated the 1H—NMR spectra of [2.2]para-cyclophane and nuclear-substituted derivatives. 

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