The para-substituted phenols

The population of the V(C, H) basins are all close to 2.10 within the accuracy of the integration scheme, and therefore it is not possible to draw any conclusion about their behaviour. 

The ELF population analysis enables one to show the following cooperative trends, which are in agreement with chemical intuition  

FIGURE 16 (PLATE 5). Localization domains of meta-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, t)(r) = 0.659 corresponds to the critical point of index 1 on the separatrix 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 23. Basin populations N(V) and electrophilic substitution positional indices RIc of meta-substituted phenols 

Values taken from Reference 220 with permission. 

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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 ... 

The steric bulk of the perfluoroalkyl group can be demonstrated by examining crystal structures of suitable compounds. For example, the crystal structure of the para-substituted phenol clearly shows the size of the C6F13 group with respect to the aromatic ring (Figure 3.5). 

The para substituted phenol (7) gives the o-diphenoquinone (8) in high yield. "... 

Furthermore, /8-cyclodextrin shows superb selectivity in the syntheses of 2.5-cyclohexadienones (12), which are important starting materials for the syntheses of physiologically active compounds, from p-substituted phenols, chloroform, and sodium hydroxide (Scheme 7) [25]. The selectivity of the production of 12 in the presence of /8-cyclodextrin is virtually 100%, in contrast to the formation of large amounts (about 4-8 times as large as 12) of orrAo-formulated compound 13 in its absence. The remarkable selectivity in the present reaction is probably due to the formation of dichlorocarbene from chloroform and hydroxide ion in the cavity of /8-cyclodextrin. The para-substituted phenol should approach the cavity (and thus the carbene) from the side involving the para-carbon, resulting in a selective reaction. The penetration of this apolar side in the apolar cavity should be more favorable than the penetration of the polar side by the phenoxide atom. 

When = H, the dienone (2), usually known as the orf/zo-dienone, rapidly tautomerizes to the 2-(prop-2-enyl)-phenol (3). This overall process is known as the orf/zo-Claisen rearrangement. If H, the dienone (2) undergoes a Cope rearrangement to give a 4-(prop-2-enyl)-cyclohexa-2,5-dienone (4), usually termed the para-dienone. The para-dienone (4) rapidly tautomerizes to the para-substituted phenol (5), and this overall transformation is termed the para-Claisen rearrangement (Scheme 3.22). 

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

In the 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 theorpara substitution is similar. The intermediate o-hydroxybenzal chloride anion (I) may react either with a hydroxide ion or with water to give the anion of salicyl-aldehyde (II), or with phenoxide ion or with 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 phenol this probably accounts for the recovery of much unreacted phenol from the reaction. 

The solubihty of alkylphenols in water falls off precipitously as the number of carbons attached to the ring increases. They are generally soluble in common organic solvents acetone, alcohols, hydrocarbons, toluene. Solubihty in alcohols or heptane follows the generalization that "like dissolves like." The more polar the alkylphenol, the greater its solubihty in alcohols, but not in ahphatic hydrocarbons likewise with cresols and xylenols. The solubihty of an alkylphenol in a hydrocarbon solvent increases as the number of carbon atoms in the alkyl chain increases. High purity para substituted phenols, through Cg, can be obtained by crystallization from heptane. 

These intermediates are too small to be used alone, but need to be enlarged and modified to obtain compatibility with other resins. In the case of the phenol formaldehyde resins this is achieved by either using para-substituted phenols where the substituent contains at least four carbon atoms or by reacting the intermediate with the natural resin, rosin, and then esterifying with glycerol or pentaerythritol. These resins have a limited use in stoved epoxy finishes where colour is not an important factor. 

Merlic et al. were the first to predict that exposing a dienylcarbene complex 126 to photolysis would lead to an ort/zo-substituted phenolic product 129 [74a]. This photochemical benzannulation reaction, which provides products complementary to the classical para-substituted phenol as benzannulation product, can be applied to (alkoxy- and aminocarbene)pentacarbonyl complexes [74]. A mechanism proposed for this photochemical reaction is shown in Scheme 54. Photo activation promotes CO insertion resulting in the chromium ketene in-... 

C—H bonds. Phenol, mono-ortho, and di- and tri-substituted phenolic rings can be monitored between 814-831, 753-794, 820-855, and 912-917 cm-1, respectively. Para-substituted phenolic rings also absorb in the 820-855-cm 1 region. 

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. 

Tables XXVIII and XXIX, respectively. Excellent correlations were obtained for all three sets. The stereochemistry of the sy -methyl ketoximes is discussed by Charton and Charton (73). The values of pj obtained for the trans-heterovinylene sets are not in good agreement with each other. Two sets gave values of 54 and 55, respectively, and the third set gave a value of 35. The difference in pj values cannot be accounted for. A value of 54 to 55 for pj suggests the possibility of some exaltation between substituent and reaction site such as that which occurs in para-substituted phenols and anilines. To demonstrate this with certainty requires that the value of pj be determined for a set of imines bearing a reaction site on the nitrogen which will not interact strongly with substituents. No such set of data is extant in the literature at the present time.

In 1996, the first successful combination of an enzymatic with a nonenzymatic transformation within a domino process was reported by Waldmann and coworkers [6]. These authors described a reaction in which functionalized bicy-clo[2.2.2]octenediones were produced by a tyrosinase (from Agaricus bisporus) -catalyzed oxidation of para-substituted phenols, followed by a Diels-Alder reaction with an alkene or enol ether as dienophile. Hence, treatment of phenols such as 8-1 and an electron-rich alkene 8-4 in chloroform with tyrosinase in the presence of oxygen led to the bicyclic cycloadducts 8-5 and 8-6 in moderate to good yield (Scheme 8.1). It can be assumed that, in the first step, the phenol 8-1 is hydroxylated by tyrosinase, generating the catechol intermediate 8-2, which is then again oxidized enzy-... 

Local HSAB principle can also be used to calculate the relative homolytic bond dissociation energies (BDE). For the homolytic dissociation of para-substituted phenols ... 

In unsubstituted phenyl ethers, the enolisation is faster than the Cope reaction. This is why the product is predominantly ortho isomer. When both the ortho positions are substituted, the allyl group undergoes a second migration via a concerted sigmatropic mechanism giving a para substituted phenol. This is called para Claisen condensation. 

The major activity in gas-phase studies now depends on the use of modem techniques such as ion cyclotron resonance (ICR). Thus, as already mentioned (Section ELD). Fujio, Mclver and Taft131 measured the gas-phase acidities, relative to phenol, of 38 meta- or para-substituted phenols by the ICR equilibrium constant method, and their results for +R substituents led them to suggest that such substituents in aqueous solution exerted solvation-assisted resonance effects. It was later163 shown by comparison of gas-phase acidities of phenols with acidities of phenols in solution in DMSO that solvation-assisted resonance effects could also occur even when the solvent did not have hydrogen-bond donor properties. Indeed for p-NC>2 and certain other substituents these effects appeared to be larger than in aqueous solution. 

Cyclohexadienones 61 and 64 are readily available from monoprotected hydro-quinones or para-substituted phenols, respectively. Conjugate additions to these symmetrical dienones result in desymmetrization of the prochiral dienone moieties, providing access to multifunctional chiral synthons in two steps from the aromatic precursors (Scheme 7.17) [72]. 

Baekeland recognized that the trifunctional phenol would produce network polymers and therefore used difunctional ortho- or para-substituted phenols to produce linear paint resins. Linear thermoplastic products are formed by alkaline or acid condensation of formaldehyde with phenol derivatives such as /r-cresol (structure 4.81). 

Fungal laccases readily oxidize ortho- and para-substituted phenols (45-48), such as syringic (15) and sinapic (13) acids, to the corresponding quinones. Experiments with Triticum vulgare... 

Two additional synthetic routes to ( )-j8-vetivone (350) have been developed. In one of these a suitably substituted spirocyclic system [cf. (349)] is constructed by addition of Me2CuLi to the fulvene derivative (348)/ Subsequent functional group modification (cf. Scheme 32) provides ( )-j8 -vetivone (350). In the other total synthesis d the well-known intramolecular alkylation of para-substituted phenols has been used to produce a spirocyclic intermediate (353) which can be converted into ( )-/3-vetivone (350) (cf. Scheme 33). 

Fukuzumi and Itoh have jointly reported on a if-peroxo dicop-per(ll) complex that acts as a functional model for the phenolase activity of tyrosinase. lithium salts of para-substituted phenols were used as substrates, reaching yields between 60 and 90% with only the catechol product formed... 

A Cope rearrangement leading to a para-substituted phenol 5.64 takes place when aromatization is not possible after the Claisen step 5.62 — 5.63. A longer conjugated system 5.65 allows a more direct delivery to the... 

The results of experiments concerning the relation between the values of the constants and the chemical nature of various compounds were also reported.88-67 The value of kg for para substituted phenols appeared to depend on the size of the substituent grouping rather than on its electronic nature, while the value of k, was not simply related to either. Further studies of this type may elucidate the significance of the constants derived and may throw light on the mechanism of the processes involved. 

In order to gain insight into how peroxynitrite attacks activated aromatic substrates, Nonoyama and co-authors (1999) examined the kinetic features of the reaction of peroxynitrite with para-substituted phenols. The authors used ONOONa as a reagent. The latter was prepared by ozonolysis of sodium azide in aqueous solution at pH 12. The reactions... 

Titanium dioxide photocatalytic oxidation of para-substituted phenols was studied by O Shea and Cardona (1994). The phenols were irradiated with UV light from mercury lamps emitting light at a wavelength of 350 nm. The phenols were studied in aqueous solution with an initial concentration of 0.1 M. TiOz was added to the solution at 0.1 g/L. The phenols were placed in the photoreactor for 30 min and then analyzed by gas chromatography to determine phenol concentrations. 

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