Anisole meta substitution

Formation of cyclohexadiene 173 by protonation is a useful reaction. Cyclohex-enone can be prepared from anisole by this reaction. Meta-substitution of the... 

Activation of aromatic compounds by transition-metal complexes was initially studied with Cr(CO)3 complexes. Nucleophilic addition of 2-lithio-l,3-dithianes to arene-chromium(O) complexes 185 followed usually by iodine-promoted decomplexation affords the corresponding 2-arylated 1,3-dithianes 186. The reaction of //-(toluene)- and (anisole)tricarbonylchromium (185) with compound 161 gave mixtures (52 46 and 10 90, respectively) of ortho and meta substituted derivatives (186) (Scheme 54)244. The meta directing effect was also observed (mainly better than 95%) with amino and fluoro substituted complexes245. 

Selectivity is more complicated with a methyl or chloro substituent. Again, meta substitution is always significant, but ortho substitution can account for 50-70% of the mixture in some cases [2]. More reactive anions (1,3-dithianyl) and less substituted carbanions (e.g., tert-butyl lithioacetate) tend to favor ortho substitution. Representative examples are shown in Table 3. Entries 2-4 show that variation of reaction temperatures from -100 °C to 0 °C has no significant effect in that highly selective system. The added activating effect of the Cl substituent allows addition of the pinacolone enolate anion (entry 11), whereas no addition to the anisole nor toluene ligand is observed with the same anion. 

Other arenechromium tricarbonyls. Semmelhack has extended his study of the reactions of carbanions with benzenechromium tricarbonyl to anisole-and toluenechromium tricarbonyl. The distribution of products depends on the particular anion used, but almost complete absence of para-substitution is consistently observed. A preference for meta-substitution over orfAo-substitution is general. 

The use of 7r-arene-Cr(CO)3 complexes in organic synthesis continues to attract attention. Carbanion attack on 7r-anisole- and 7r-toluene-chromium tricarbonyl complexes gives, after oxidative work-up, meta-substituted aromatics as the major product [equation (24)]. With the anisole complex the me/a-substituted product... 

At first glance, substitution at the para position of anisole seems similar to meta substitution (Fig. 14.65). But look carefully at the intermediate in para substitution and remember our discussion of the stabilization of carbocations that are adjacent to an oxygen (p. 378). In the intermediate from para substitution, there is a fourth resonance form in which oxygen shares the positive charge... 

Because the intermediate formed in para (or ortho) substitution of anisole is more stable than that formed in meta substitution of anisole or in substitution of benzene, the transition state leading to the para (or ortho) intermediate is more stable than the transition states for meta substitution of anisole or substitution of benzene itself... 

FIGURE 14.67 The intermediate for para substitution, with four resonance forms, is lower in energy than the intermediate for meta substitution (three forms) or that for substitution of benzene (also three forms). The transition state for para substitution of anisole will also be lower in energy than the transition state for meta substitution. 

All the syntheses of tricyclic ketones in Scheme 8 described so far have been carried out from comparatively poorly accessible meta-substituted anisoles. Consequently, the possibility of using themore accessible para-substituted anisoles as starting materials offered considerable interest [219]. The acylation of anisole (82) with glutaric anhydride, esterification, the Stobbe reaction, and hydrolysis led to the triacid (87). 

The fluorination of other activated aromatic compounds, such as anisole and phenol, undergo monofluorination mainly in the ortho and para positions, whereas the fluorination of deactivated aromatics, such as nitrobenzene, trifluoromethylbenzene and benzoic acid, give predominantly the corresponding meta fluoro-derivatives which is consistent with a typical electrophilic substitution process. Also, fluoro-, chloro- and bromo-benzenes are deactivated with respect to benzene itself but are fluorinated preferentially in the ortho and para positions [139]. At higher temperatures, polychlorobenzenes undergo substitution and addition of fluorine to give chlorofluorocyclohexanes [136]. 

Competition reactions between benzene and various substituted benzenes reveal that electron-withdrawing substituents on the arene increase reaction rates. All ortho, meta, and para forms of the arylsilanes are obtained. The major component of the arylsilane product formed in reactions of arylsilanes with electron-withdrawing groups, such as chlorobenzene, and anisole, is the ortho isomer. In contrast, toluene, which bears a less electronegative substituent, leads to meta isomer as major product. 

In the case of anisole, the reaction takes following route shown in Scheme 4-10. The reaction yields only products of the ortho and para substitutions the meta isomer is lacking. If it were a standard radical substitution, the meta isomer would obviously be formed in a certain amount (i.e., in the same amount as that for ortho-substituted product). 

A correlation for less structurally related compounds was also developed by Amalric et al. (1996). To develop this correlation, meta- and para-substituted anisoles were studied. These aromatic compounds were substituted with F, Cl, N02, OH, and NH2 groups. The first-order degradation rate constant, kapf was predicted with the octanol/water partition coefficient (log Kow), Brown s constant (o+), and molar refractivity (MR) used as descriptors. The following correlation was developed ... 

The correlation was developed with a correlation coefficient of 0.903. The correlation was able to accurately predict the first-order degradation rate constants as a function of Brown s constant, the octanol/water partition coefficient, and molar refractivity. This correlation held for a broader class of aromatic compounds substituted at the meta and para positions, as compared to a simple substitution at one position on the aromatic ring. Table 9.6 lists the experimental and predicted values for the first-order degradation rate constants of substituted anisoles. 

Experimental and Predicted Values of Meta- and Para-Substituted Anisoles... 

Similar results were obtained [139] with the three dimethoxybenzenes and acrylonitrile, methacrylonitrile, and crotonitrile. The amounts of substitution products decrease in the order acrylonitrile (49%) > methacrylonitrile (45%) > crotonitrile (6%), which agrees with the electron affinities of these compounds. Simultaneously, the amount of addition product increases acrylonitrile, 0% methacrylonitrile, 38% crotonitrile, 67%. In the series of anisole and the dimethoxybenzenes with crotonitrile, the amount of substitution products decrease in the order ortho- and para-dim ethoxy benzene > meta-dimethoxyben-zene > anisole, which is just the reverse of the order of their oxidation potentials. Ohashi et al. [139] have attempted to relate the photochemical behavior of these systems to the free enthalpy of electron transfer in the excited state as calculated with the Rehm-Weller equation, AG = E(D/D+) - E(A /A) - el/eR - AE00. 

The meta photocycloaddition is frequently observed in cases of alkyl or electron-donor substituted benzene derivatives. Two exo/endo isomeres 2a,b are obtained in high yields in the reaction of anisole 1 with cyclopentene (Sch. 2) [18]. The reaction was also efficiently carried out in an intramolecular way. Two efficient reactions of this type are depicted in Sch. 2. The azatriquinane 3 [19] and the silane derivative 4 [20] were obtained in high yields. The formation of different regioisomers can be controlled by the heteroatoms in the side chain. The longer C-Si bonds particularly favor the formation of compound 4. 

The reaction of MeO involves direct ipso substitution, as shown by the reactions of meta-and para-chlorotoluenetricarbonylchromiums 14b and 14c, which give meta- and para-anisole derivatives 15b and 15c, respectively. It is interesting at this stage to point out that... 

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