The ortho-substituted phenols

Let us consider first the trans conformers in which the halogen substituent is not perturbed by an extra intramolecular interaction. In all molecules the V(Ci, O) basin population is slightly increased with respect to phenol the largest effect occurs for X = Cl, whereas for X = Br and I this effect is weaker than for the fluorinated species. The 

FIGURE 15 (PLATE 4). Localization domains of ort/io-X-substituted phenols (from left to right X = F, Cl, Br, I top—trans conformer, bottom—cis conformer). The ELF value defining the boundary isosurface, j(r) = 0.659 corresponds to the critical point of index 1 on the separatiix between adjacent V(C, C) basins of benzene. Colour code magenta = core, orange = monosynaptic, blue = protonated disynaptic, green = disynaptic. Adapted from Reference 220 with permission 

TABLE 22. Basin populations N(Y) and electrophilic substitution positional indices RIc of ortho-substituted phenols 

Values taken from Reference 220 with permission. 

X) populations are close to their values in the corresponding halobenzene however, there is a small electron transfer towards this basin for X = F, whereas the iodine atom undergoes an opposite effect. With respect to phenol, the regioselectivity of the electrophilic substitution is softened because as the OH and X = F, Cl, Br groups are both ortho-para directors, they contribute in opposite directions. As all the positional indices of CeHsI are positive, they are enhanced in the trans orf/io-iodophenol. The additive rule works satisfactorily for all positions as the largest discrepancy between estimated and calculated value does not exceed 0.002. 

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An intriguing method for preparing phenolic nitroso compounds was discovered by Baudisch [95]. Interestingly enough, the product mixture from the reaction appears to be primarily the ortho-substituted phenol, a class of compounds of which very few examples seem to have been described. 

Under comparable reaction conditions the much more reactive formaldehyde and phenol do not only give the para- but also the ortho-substituted phenol derivative. This reaction ultimately leads to the three-dimensional network of formaldehyde/phenol condensation resins such as Bakelite and to related, well-defined receptor molecules known as cahxarenes. 

In the propionic acid catalyzed hydroxyalkylation, benzene boronic acid directed the aldehyde into the ortho position via the boronic ester 449 and led to very good yields of the ortho-substituted phenols 450 [153]. 

These intermediates of type 451 can be generated with an aza sulfonium salt and are in situ carried along to the ortho-substituted phenol 452. 

Some ortho substituted phenols such as o mtrophenol have significantly lower boiling points than those of the meta and para isomers This is because the intramolec ular hydrogen bond that forms between the hydroxyl group and the substituent partially compensates for the energy required to go from the liquid state to the vapor... 

If both ortho positions bear substituents other than hydrogen, the allyl group will further migrate to the para position. This reaction is called the para-Claisen rearrangement. The formation of the para-substituted phenol can be explained by an initial Claisen rearrangement to an ortho-2l y intermediate which cannot tautomerize to an aromatic o-allylphenol, followed by a Cope rearrangement to the p-allyl intermediate which can tautomerize to the p-allylphenol e.g. 6 ... 

Because steric factors strongly influence the rate of silylations, primary alcohols are normally silylated much more rapidly than secondary alcohols whereas tertiary alcohols are silylated much more slowly. The same is true for phenols - ortho-substituted phenols such as o-cresol are silylated much more slowly than unsubstituted phenols. Obviously, the same applies to cleavage of silylated alcohols or phenols on transsilylation, e.g. with excess boiling methanol (Section 2.3). 

A spore-forming strain of Desulfitobacterium chlororespirans was able to couple the dechlorination of 3-chloro-4-hydroxybenzoate to the oxidation of lactate to acetate, pyruvate, or formate (Sanford et al. 1996). Whereas 2,4,6-trichlorophenol and 2,4,6-tribro-mophenol supported growth with the production of 4-chlorophenol and 4-bromophenol, neither 2-bromophenol nor 2-iodophenol was able to do so. The membrane-bound dehalogenase contains cobalamin, iron, and acid-labile sulfur, and is apparently specific for ortho-substituted phenols (Krasotkina et al. 2001). 

Desulfitobacterium chlororespirans can use ortho-substituted phenols as electron acceptors for anaerobic growth, and is able to debrominate 2,6-dibromo-4-cyanophenol (Bromoxynil) and 2,6-dibromo-4-carboxyphenol. In contrast, 2,6-diiodo-4-cyanophenol (loxynil) was deiodinated only in the presence of 3-chloro-4-hydroxybenzoate (Cupples et al. 2005). 

In tile strongly basic medium, the reactant is the phenoxide ion high nucleophilic activity at the ortho and para positions is provided through the electromeric shifts indicated. The above scheme indicates the ortho substitution the para substitution is similar. The intermediate o-hydroxybenzal chloride anicxi (I) may react eitho with a hydroxide ion or with water to give the anion of saliwith phenol to give the anion of the diphenylacetal of salicylaldehyde (III). Both these anions are stable in basic solution. Upon acidification (III) is hydrolysed to salicylaldehyde and phaiol this probably accounts for the recovery of much unreacted phenol from the reaction. 

Tab. 10.7 summarizes the results of the application of rhodium-catalyzed allylic etherification to a series of ortho-substituted phenols. The etherification tolerates alkyls, including branched alkanes (entries 1 and 2), aryl substituents (entry 3), heteroatoms (entries 4 and 5), and halogens (entry 6). These results prompted the examination of ortho-disubstituted phenols, which were expected to be more challenging substrates for this type of reaction. Remarkably, the ortho-disubstituted phenols furnished the secondary aryl allyl ethers with similar selectivity (entries 7-12). The ability to employ halogen-bearing ortho-disubstituted phenols should facilitate substitutions that would have proven extremely challenging with conventional cross-coupling protocols. 

If both ortho positions are substituted, the allyl group undergoes a second sigmatropic migration, giving the / ara-substituted phenol ... 

The metalloporphyrin-initiated polymerizations are accelerated by the presence of steri-cally hindered Lewis acids [Inoue, 2000 Sugimoto and Inoue, 1999]. The Lewis acid coordinates with the oxygen of monomer to weaken the C— O bond and facilitate nucleophilic attack. The Lewis acid must be sterically hindered to prevent its reaction with the propagating center attached to the prophyrin structure. Thus, aluminm ortho-substituted phenolates such as methylaluminum bis(2,6-di-/-butyl-4-methylphenolate) accelerate the polymerization by factors of 102-103 or higher. Less sterically hindered Lewis acids, including the aluminum phenolates without ortho substituents, are much less effective. 

Now we consider the solvent effects on the mutual relationship between the p/C, values of different adds. Figure 3.2 shows the relations between pfC, of non-ortho-substituted phenols and the Hammett er-values of the substituents [8]. Good linear relations are observed in four solvents.3 It is of special interest that the slopes in AN, DMF and DMSO are almost the same and are nearly 2.0 times the slope in water. Similar linear relations have also been obtained for non-ortho-sub-... 

Fig. 3.2 Relations between the pKa values of non-ortho-substituted phenols and the Hammett rr-values of the substituents [8]. Substituents 1, none 2, 4-chloro 3, 4-bromo 4, 3-chloro ...

Some compounds, such as highly substituted alcohols and ortho substituted phenols, are unable, for steric reasons, to form polymeric hydrogen bonded species, and hence they exist only as dimers which gives rise to sharp absorption in the 3550-3450cm-1 region. In these instances hydrogen bonds are also broken on dilution with the consequence that the absorption intensity and position change. 

Ortho-substituted phenolic diesters, such as bis-p-(l,4-butyroyl)-2-octylhydro-quinone (Figure 12.9), can be hydrolyzed in the more hindered 1-position or in the less-hindered 4-position. The regioselectivity of hydrolysis to the monoester, as expressed by the ratio of kcM/Ku values, depends approximately linearly on log P over the range from acetonitrile (log P -0.33) to cyclohexane (log P 3.2), and is thus controlled by the hydrophobicity of the solvent (Rubio, 1991). 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

In a recent paper, the same authors showed that iron(III) chloride can mediate the oxidative coupling of substituted aryl ethers with an observed regioselectivity that depends on the substitution pattern [66] meta-substituted phenol ethers 77 led to polymers (Scheme 18a) whereas para-substituted phenol ether 79 gave predominantly biphenyl structures (Scheme 18b). ortho-Substituted phenol ether 81 provided a dimer with the Ar-Ar bond at a position para to one of the methoxy substituents (Scheme 18c). 

The Reimer-Tiemann reaction used to be an important way of making ortho-substituted phenols, but the yields are often poor, and modern industly is wary of using large quantities of chlorinated solvents. On a small, laboratory scale it has largely been superseded by ortholithiation (Chapter 9) and by modern methods outside the scope of this book. The mechanism probably goes something like this. 

By virtue of the intramolecular anchoring bonding, sp C-H bond activation may become possible. Treatment of Ru(l,5-COD)(l,3,5-COT) with (ortho)-substituted phenols resulted in the successive O-H and sp C-H bond-cleavage reactions, giving... 

For the alkylation of the more active phenol both Bronsted and Lewis acid sites are claimed to participate in the catalytic activation [111]. The Bronsted acid sites activate the alkylating agent by protonation, whereas the Lewis acid sites can activate the alkylating agent and phenol by coordination, and/or phenol by deprotonation. If activation of the alkylating agent and the phenol occurs on the same Lewis acid site, the predominant product will be the ortho- substituted isomer. 

With the simple aryl halides such as the mono-chlor derivatives of benzene or its homologues this reaction does not take place. Tf, however, a benzene halide has also substituted in the ring two nitro, sul-phonic acid or carboxyl groups, in the ortho and para positions to the halogen, then treatment of the halide with potassium hydroxide results in replacing the halogen with hydroxyl and the corresponding substituted phenol will be obtained. 

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