Ortho-substituted phenols

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). 

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... 

Halogenation Bromination and chlorination of phenols occur readily even in the absence of a cata lyst Substitution occurs primarily at the position para to the hydroxyl group When the para position IS blocked ortho substitution is observed... 

Metal hydroxides of first- and second-group elements can enhance ortho substitution, the degree of which depends on the strength of metal-chelating effects linking the phenolic oxygen with the formaldehyde as it approaches the ortho position. Transition metal ions of elements such as Fe, Cu, Cr, Ni, Co, Mn, and Zn as well as boric acid also direct ortho substitutions via chelating effects (Fig. 7.9). 

Resole syntheses entail substitution of formaldehyde (or formaldehyde derivatives) on phenolic ortho and para positions followed by methylol condensation reactions which form dimers and oligomers. Under basic conditions, pheno-late rings are the reactive species for electrophilic aromatic substitution reactions. A simplified mechanism is generally used to depict the formaldehyde substitution on the phenol rings (Fig. 7.21). It should be noted that this mechanism does not account for pH effects, the type of catalyst, or the formation of hemiformals. Mixtures of mono-, di-, and trihydroxymethyl-substituted phenols are produced. 

Crosslinking resoles in the presence of sodium carbonate or potassium carbonate lead to preferential formation of ortho-ortho methylene linkages.63 Resole networks crosslinked under basic conditions showed that crosslink density depends on the degree of hydroxymethyl substitution, which is affected by the formaldehyde-to-phenol ratio, the reaction time, and the type and concentration of catalyst (uncatalyzed, with 2% NaOH, with 5% NaOH).64 As expected, NaOH accelerated the rates of both hydroxymethyl substitution and methylene ether formation. Significant rate increases were observed for ortho substitutions as die amount of NaOH increased. The para substitution, which does not occur in the absence of the catalyst, formed only in small amounts in the presence of NaOH. 

Another hydroxylation reaction is the Elbs reaction In this method, phenols can be oxidized to p-diphenols with K2S20g in alkaline solution. Primary, secondary, or tertiary aromatic amines give predominant or exclusive ortho substitution unless both ortho positions are blocked, in which case para substitution is found. The reaction with amines is called the Boyland-Sims oxidation. Yields are low with either phenols or amines, generally under 50%. The mechanisms are not clear, but for the Boyland-Sims oxidation there is evidence that the S20 ion attacks at the ipso position, and then a migration follows. ... 

Anaeromyxobacter dehalogenans This organism that is able to use ortho-substituted phenols for chlororespiration is able to use various forms of Fe(III) (He and Sanford 2003). 

A facultatively anaerobic organism designated Anaeromyxobacter dehalogenans (Sanford et al. 2002) was capable of dechlorinating ortho-chlorinated phenols using acetate as electron donor—2-chlorophenol was reduced to phenol and 2,6-dichlorophenol to 2-chloro-phenol (Cole et al. 1994). A strain of Desulfovibrio dechloracetivorans was also able to couple the dechlorination of ortho-substituted chlorophenols to the oxidation of acetate, fumarate, lactate, and propionate (Sun et al. 2000). 

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. 

The data in Table I are not directly comparable, since the viscosity of the 3-isomer was determined in benzene while the others were measured in DMSO. In addition, the first two polymers were prepared in bulk polymerizations, while the polymerization of methyl 3-vinylsalicylate was carried out with the monomer diluted 1 1 with benzene. Thus no certain conclusion can be drawn the data are, however, an indication of possible difficulty in radical polymerization of substituted styrenes bearing a phenol ortho to the vinyl group. 

Schaefer T (1975) A relationship between hydroxyl proton chemical shifts and torsional frequencies in some ortho-substituted phenol derivatives. J Phys Chem 79 1888-1890... 

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. 

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. 

Phenols undergo electrophilic substitutions. In phenol, the substitutions take place in ortho and para positions. As the —OH group is an activating group, the reaction rate is much faster than usually observed with benzene. For example, the bromination of phenol produces ort/io-bromophenol (12%) and para-bromophenol (88%). 

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. 

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 ...

We have stated earlier that because of proximity effects, no generally applicable aj values may be derived for ortho substitution. Nevertheless, one can determine a set of apparent 0)ortho values for a specific type of reaction, as for example, for the dissociation of substituted phenols. Table 8.7 gives such apparent O)ortho constants for estimating pKa values of substituted phenols and anilines. Of course, in cases of multiple substitution, substituents may interact with one another, thereby resulting in larger deviations of experimental from predicted pKa values. Some example calculations using the Hammett equation are given in Illustrative Example 8.2. 

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