Substituted phenol

A wide range of substituted phenols has been used for treatment of liver flukes and tapeworms in animals. Most drugs within this group have a low safety index 

Studies on the composition of nitroxynil-related residues in calves and sheep after subcutaneous treatment showed that the unchanged nitroxynil was the major component of the residues in calf kidney, muscle, and fat, accounting for around 56%, 69%, and 78% of the total residues, respectively. The 4-cyano- 

Nitroxynil has a tendency to bind strongly to proteins and therefore is retained in animal tissues and milk for long periods after its administration (8). Residue depletion studies in cattle subcutaneously treated with nitroxynil showed that kidney contained 252, 107, and 90 ppb, muscle 149-587, 89-131, and 50, and the injection site 90-504, 90-207, and 90 ppb of the parent drug 

Dichlorophen is a safe, narrow-spectrum drug that, in addition to its bactericidal and fungicidal properties, has been used as a teniacide in veterinary medicine for many years. It is administered to sheep as a tablet or suspension at a dosage of 0.5g/2.5 kg bw. The insolubility of dichlorophen in water limits its absorption from the gastrointestinal tract and probably accounts for its low toxicity. Worms are killed in the gut where they disintegrate prior to expulsion in the feces. 

We have seen above (p. 398) how three hi- and tri-substituted derivatives are derivable from benzene. Phenol is a nnisubsti-tuted derivative of the same substance and hence still contains, five H atoms which may be replaced by other elements or radicals, to produce di- or tri- or poly-substituted derivatives of benzene, which will be ortho, ineta or para, etc., according to the relations of the introduced groups to the OH, already existing in phenol, or to the CiJIsn+i and OH groups in its superior hoinologues. 

Chlorophenols.—The three inonochlorinated compounds are obtainable from the corresponding ohloranilins. Orthoohloro-phenol (1—2) is a colorless liquid, boils atl7o°-170° (347°-848°.8 P.), converted into catechol by KHO. Metachlorophenol (1—3) is a liquid, boiling at 214° (417°.2 F.). KHO converts it into resorcin. Parachlorophenol (1—4) is a crystalline solid, fusible at 37° (98°. C F.), converted into quinol by fusion with KHO. Di-, tri-, and penta-ohlorophenols are also known. 

Bromophenols correspond in method of formation and properties with the Cl derivatives. 

Nitre-phenols—Hononitro-phenols—CoHitNOalOH—(1—2), (1—3) and (1—4) are formed by the action of HNOs on CoHsOH. The ortho compound (1—2) crystallizes in large yellow needles, sparingly soluble, and capable of distillation with steam. The meta. and x ara compounds are both colorless, non-volatile, crystalline bodies. Two dinitro-phenols, C HsOH(I10j)5(j-o and CeHa 0H(N02)j(j—0), are obtained by the action of strong nitric acid on phenol, or on ortho- or para-mononitro phenol. They are both solid, crystalline substances, converted by further nitration into picric acid. 

Trinitro-phenols—C6H2(NOj)sOH.—Two are known (1.) Picric acid—Carbazotic acid—Trinitro-phenic acid—(NOa) in 2—4—0. It-is formed by nitrification of phenol, or of 1—2—4 or 1—2—6 dinitro-phenols, and also by the action of HKOs on indigo, silk, wool, resins, etc. It crystallizes in brilliant, yellow, rectangular plates, or in six-sided prisms it is odorless, and has an intensely bitter taste, Avhence its name (from mKpbg — bitter) it is acid in reaction sparingly soluble in water, very soluble in alcohol, other, and 

While the linkage structure of the phenol polymers made from p-sub-stituted phenols was not investigated in detail in most cases, recent studies have shown clear evidence that the polymerization of p-substituted phenols leads preferentially to ortho-ortho coupling during the initial stage of the polymerization [46,76]. In contrast, it was also reported that the polymerization of p-substituted phenols may lead to polymers that consist (according to 

This observation can be explained by the appearance of different kinds of electrophilic or more nucleophilic radicals. The electron-rich phenol is attacked by highly electrophilic radicals, while the methacrylic group is selectively attacked by less electrophilic radicals (e.g., R-0, C), which are generated for instance during an AIBN initiation. The recombination of two phenoxy radicals is for that reason more likely than the attack of a phenoxy radical on the electron-poor methacryhc double bond [48]. 

All phenol polymers having free vinyl groups in the side chain (50, 56, and 57) could be furthermore subjected to thermal ciu ing due to cross-linking through the methacryhc groups [47,48]. A multi-methacrylate ohgomer was also prepared by polymer-analogous fimctionahzation of a poly(isopropylidenediphenol) (BPA) resin. Such materials could be of potential interest for the formulation of dental composites as direct esthetic restorative materials [15]. 

Another way to realize thermally cross-finkable phenol copolymers was reached via the 1,3-dipolaric cycloaddition reaction between phenols having a vinyl group (55, 56) and phenols bearing a nitrone group (65), which act as a 1,3-dipole [74]. These materials were readily cross-linked at room temperature. 

Altogether, there have been only a few studies published dealing with the copolymerization behavior of distinct phenols, and usually the characterization of the copolymers was not fully examined. An early study of copolymerizations between different phenols and anifines can be found, wherein the copolymer compositions were characterized by elemental analysis [78]. In addition, monomeric phenols have been copolymerized with phenol polymers. This procedure offers, for example, an interesting way to turn fignin, a polymeric by-product from the pulp and paper industry, into a technical material. Lignin was reacted with phenol in an HRP-catalyzed copolymerization to produce lignin phenolic resins [117]. 

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Antioxidant and deactivation additives substituted phenols, dithiophosphates, dithiocarbamates, alkylated aromatic amines. 

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

The Reaction has the following limitations (i) a compound that can liberate nitrous acid in acid solution is required (e.g., a metallic nitrite or a nitroso-amine, p. 204). (2) Nitrophenols and />-substituted phenols do not give the test. (3) Among the dihydroxyphenols. only resorcinol gives a satisfactory positive test. 

Note. Some substituted phenols, particularly nitrophenols, are sufficiently acidic to liberate CO, from Na,CO,. Nitrophenols, however, all give yellow or red solutions with NajCOj. 

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

Acetates. The acetates of monohydric phenols are usually liquids, but those of di and tri-hydric phenols and also of many substituted phenols are frequently crystaUine sohds. They may be prepared with acetic anhydride as detailed under Amines, Section IV,100,7. 

RCH(OH)=CHCOR or -keto esters RCH(OH)=CHCOOR ) dissolve in dilute sodium hydroxide solution, i.e., contain an acidic group of sufficient strength to react with the alkah. Carboxyhc acids and sulphonic acids are soluble in dilute solutions of sodium bicarbonate some negatively-substituted phenols, for example, picric acid, 2 4 6-tribromo-phenol and 2 4-dinitrophenol, are strongly acidic and also dissolve in dilute sodium bicarbonate solution. 

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... 

Calixarenes (from the Latin ca/ x) may be understood as artificial receptor analogues of the natural cyclodextrins (96,97). In its prototypical form they feature a macrocycHc metacyclophane framework bearing protonizable hydroxy groups made from condensation of -substituted phenols with formaldehyde (Fig. 15b). Dependent on the ring size, benzene derivatives are the substrates most commonly included into the calix cavity (98), but other interesting substrates such as C q have also been accommodated (Fig. 8c) (45). 

In general, the xanthenes are synthesized by the reaction of two moles of a nucleophilic / -substituted phenol (10) with an electrophilic carbonyl compound (11), the reaction occurring most readily with an acid catalyst at temperatures of 100—200°C. 

Aminohydroxy-substituted xanthenes ate of Httle commercial importance. They are synthesized by condensing one mole of y -diaLkylaminophenol with phthahc anhydride, and then condensing that product with an appropriately substituted phenol. For example. Mordant Red 77 [6528-43 ] (Cl45300) (45) is prepared by condensing m- dim ethyl am in opb en o1 with phthaUc anhydride, and then condensing the product with 2,4-dihydroxybenzenesulfonic acid. 

As improvements over P-methylumbeUiferone (55—57), 4-methyl-7-amino-coumarin [26093-31-2] (12a) and 7-dimethylamino-4-methylcoumarin [87-014] (12b) (58—61) were proposed. These compounds are used for brightening wool and nylon either in soap powders or detergents, or as salts under acid dyeing conditions. They are obtained by the Pechmaim synthesis from appropriately substituted phenols and P-ketocarboxyflc acid esters or nitriles in the presence of Lewis acid catalysts (see Coumarin). 

Synthetic phenol capacity in the United States was reported to be ca 1.6 x 10 t/yr in 1989 (206), almost completely based on the cumene process (see Cumene Phenol). Some synthetic phenol [108-95-2] is made from toluene by a process developed by The Dow Chemical Company (2,299—301). Toluene [108-88-3] is oxidized to benzoic acid in a conventional LPO process. Liquid-phase oxidative decarboxylation with a copper-containing catalyst gives phenol in high yield (2,299—304). The phenoHc hydroxyl group is located ortho to the position previously occupied by the carboxyl group of benzoic acid (2,299,301,305). This provides a means to produce meta-substituted phenols otherwise difficult to make (2,306). VPOs for the oxidative decarboxylation of benzoic acid have also been reported (2,307—309). Although the mechanism appears to be similar to the LPO scheme (309), the VPO reaction is reported not to work for toluic acids (310). 

Make acid yields coumaUc acid when treated with fuming sulfuric acid (19). Similar treatment of malic acid in the presence of phenol and substituted phenols is a facile method of synthesi2ing coumarins that are substituted in the aromatic nucleus (20,21) (see Coumarin). Similar reactions take place with thiophenol and substituted thiophenols, yielding, among other compounds, a red dye (22) (see Dyes and dye intermediates). Oxidation of an aqueous solution of malic acid with hydrogen peroxide (qv) cataly2ed by ferrous ions yields oxalacetic acid (23). If this oxidation is performed in the presence of chromium, ferric, or titanium ions, or mixtures of these, the product is tartaric acid (24). Chlorals react with malic acid in the presence of sulfuric acid or other acidic catalysts to produce 4-ketodioxolones (25,26). 

Carbamate Insecticides. These are stmcturaUy optimi2ed derivatives of the unique plant alkaloid physostigmine [57-47-6] a cholinergic dmg isolated in 1864 from Phjsostigma venenosum (see Alkaloids) (17,24,35—39). The carbamates maybe considered synthetic derivatives of the synaptic neurotransmitter acetylcholine, with very low turnover numbers. The A/,A/-dimethylcarbamates of heterocycHc enols (36) and the Ai-methylcarbamates of a variety of substituted phenols (35) with a wide range of insecticidal activity were described in 1954 (35). The latter are the most widely used carbamate insecticides, and the A/-methylcatbamates of oximes have subsequentiy been found to be effective systemic insecticides. 

The emission yield from the horseradish peroxidase (HRP)-catalyzed luminol oxidations can be kicreased as much as a thousandfold upon addition of substituted phenols, eg, -iodophenol, -phenylphenol, or 6-hydroxybenzothiazole (119). Enhanced chemiluminescence, as this phenomenon is termed, has been the basis for several very sensitive immunometric assays that surpass the sensitivity of radioassay (120) techniques and has also been developed for detection of nucleic acid probes ia dot-slot. Southern, and Northern blot formats (121). 

Oxidation of LLDPE starts at temperatures above 150°C. This reaction produces hydroxyl and carboxyl groups in polymer molecules as well as low molecular weight compounds such as water, aldehydes, ketones, and alcohols. Oxidation reactions can occur during LLDPE pelletization and processing to protect molten resins from oxygen attack during these operations, antioxidants (radical inhibitors) must be used. These antioxidants (qv) are added to LLDPE resins in concentrations of 0.1—0.5 wt %, and maybe naphthyl amines or phenylenediamines, substituted phenols, quinones, and alkyl phosphites (4), although inhibitors based on hindered phenols are preferred. 

Phenohc resins are produced by the condensation of phenol or a substituted phenol, such as cresol, with formaldehyde. These low cost resins have been produced commercially for more than 100 years and in the 1990s are produced by more than 40 companies in the United States. They are employed as adhesives in the plywood industry and in numerous under-the-hood appHcations in the automotive industry. Because of the cycHc nature of the automotive and home building industry, the consumption of phenol for the production of phenohc resins is subject to cycHc swings greater than that of the economy as a whole. 

PhenoHc resins are prepared by the reaction of phenol or substituted phenol with an aldehyde, especially formaldehyde, in the presence of an acidic or basic catalyst. Their thermosetting character and the exotherm associated with the reaction presented technical barriers to commercialization. In 1900, the first U.S. patent was granted for a phenoHc resin, using the resin in cast form as a substitute for hard mbber (10). 

Substituted Phenols. Phenol itself is used in the largest volume, but substituted phenols are used for specialty resins (Table 2). Substituted phenols are typically alkylated phenols made from phenol and a corresponding a-olefin with acid catalysts (13). Acidic catalysis is frequendy in the form of an ion-exchange resin (lER) and the reaction proceeds preferentially in the para position. For example, in the production of /-butylphenol using isobutylene, the product is >95% para-substituted. The incorporation of alkyl phenols into the resin reduces reactivity, hardness, cross-link density, and color formation, but increases solubiHty in nonpolar solvents, dexibiHty, and compatibiHty with natural oils. 

Table 2. Substituted Phenols Used for Phenolic Resins...

Alkaline Catalysts, Resoles. Resole-type phenoHc resins are produced with a molar ratio of formaldehyde to phenol of 1.2 1 to 3.0 1. For substituted phenols, the ratio is usually 1.2 1 to 1.8 1. Common alkaline catalysts are NaOH, Ca(OH)2, and Ba(OH)2. Whereas novolak resins and strong acid catalysis result in a limited number of stmctures and properties, resoles cover a much wider spectmm. Resoles may be soHds or Hquids, water-soluble or -insoluble, alkaline or neutral, slowly curing or highly reactive. In the first step, the phenolate anion is formed by delocali2ation of the negative charge to the ortho and para positions. 

Aqueous dispersions are alternatives to solutions of Hquid and soHd resins. They are usuaUy offered in 50% soHds and may contain thickeners and cosolvents as stabilizers and to promote coalescence. Both heat-reactive (resole) and nonheat-reactive (novolak) systems exist that contain unsubstituted or substituted phenols or mixtures. A related technology produces large, stable particles that can be isolated as discrete particles (44). In aqueous dispersion, the resin stmcture is designed to produce a hydrophobic polymer, which is stabilized in water by an interfacial agent. 

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. 

Sulfur monochloride also reacts with substituted phenols to give condensation products useful for mbber compounding (qv) (150). Elf Atochem NA manufactures products known as Vultacs by the reaction of amylphenols and sulfur monochloride (153). 

Ethyleneamines are used in certain petroleum refining operations as well. Eor example, an EDA solution of sodium 2-aminoethoxide is used to extract thiols from straight-mn petroleum distillates (314) a combination of substituted phenol and AEP are used as an antioxidant to control fouling during processing of a hydrocarbon (315) AEP is used to separate alkenes from thermally cracked petroleum products (316) and TEPA is used to separate carbon disulfide from a pyrolysis fraction from ethylene production (317). EDA and DETA are used in the preparation and reprocessing of certain... 

Dimethoxybenzyl esters prepared from the acid chloride and the benzyl alcohol are readily cleaved oxidatively by DDQ (CH2CI2, H2O, rt, 18 h, 90-95% yield). A 4-methoxybenzyl ester was found not to be cleaved by DDQ. The authors have also explored the oxidative cleavage (ceric ammonium nitrate, CH3CN, H2O, 0°, 4 h, 65-97% yield) of a variety of 4-hydroxy- and 4-amino-substituted phenolic esters. ... 

Phenols Substituted phenols 4-Methyl-2, 6-di-t-butylphenol (VI) No Often used in non-toxic formulations. Very low level of staining. Widely used to protect polymers during synthesis and fabrication. Volatility restricts high-temperature and long-term use. 

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