939 CHAPTER 24 PHENOLS P henols are compounds that have a hydroxyl group bonded directly to a benzene or benzenoid ring. The parent compound of this group, C 6 H 5 OH, called simply phe- nol, is an important industrial chemical. Many of the properties of phenols are anal- ogous to those of alcohols, but this similarity is something of an oversimplification. Like arylamines, phenols are difunctional compounds; the hydroxyl group and the aromatic ring interact strongly, affecting each other’s reactivity. This interaction leads to some novel and useful properties of phenols. A key step in the synthesis of aspirin, for exam- ple, is without parallel in the reactions of either alcohols or arenes. With periodic reminders of the ways in which phenols resemble alcohols and arenes, this chapter emphasizes the ways in which phenols are unique. 24.1 NOMENCLATURE An old name for benzene was phene, and its hydroxyl derivative came to be called phe- nol.* This, like many other entrenched common names, is an acceptable IUPAC name. Likewise, o-, m-, and p-cresol are acceptable names for the various ring-substituted hydroxyl derivatives of toluene. More highly substituted compounds are named as deriv- atives of phenol. Numbering of the ring begins at the hydroxyl-substituted carbon and proceeds in the direction that gives the lower number to the next substituted carbon. Sub- stituents are cited in alphabetical order. OH Phenol OH CH 3 m-Cresol OH CH 3 Cl 1 2 3 4 5 6 5-Chloro-2-methylphenol *The systematic name for phenol is benzenol. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The three dihydroxy derivatives of benzene may be named as 1,2-, 1,3-, and 1,4- benzenediol, respectively, but each is more familiarly known by the common name indi- cated in parentheses below the structures shown here. These common names are per- missible IUPAC names. The common names for the two hydroxy derivatives of naphthalene are 1-naph- thol and 2-naphthol. These are also acceptable IUPAC names. PROBLEM 24.1 Write structural formulas for each of the following compounds: (a) Pyrogallol (1,2,3-benzenetriol) (c) 3-Nitro-1-naphthol (b) o-Benzylphenol (d) 4-Chlororesorcinol SAMPLE SOLUTION (a) Like the dihydroxybenzenes, the isomeric trihydroxy- benzenes have unique names. Pyrogallol, used as a developer of photographic film, is 1,2,3-benzenetriol. The three hydroxyl groups occupy adjacent positions on a benzene ring. Carboxyl and acyl groups take precedence over the phenolic hydroxyl in deter- mining the base name. The hydroxyl is treated as a substituent in these cases. 24.2 STRUCTURE AND BONDING Phenol is planar, with a C±O±H angle of 109°, almost the same as the tetrahedral angle and not much different from the 108.5° C±O±H angle of methanol: O H 136 pm 109° Phenol O H 142 pm 108.5° CH 3 Methanol HO COH O p-Hydroxybenzoic acid CH 3 CCH 3 O OH 65 4 1 23 2-Hydroxy-4-methylacetophenone OH OH OH Pyrogallol (1,2,3-benzenetriol) OH OH 1 2 3 4 5 6 1,2-Benzenediol (pyrocatechol) OH OH 1 2 3 4 5 6 1,4-Benzenediol (hydroquinone) OH OH 1 2 3 4 5 6 1,3-Benzenediol (resorcinol) 940 CHAPTER TWENTY-FOUR Phenols Pyrocatechol is often called catechol. The graphic that opened this chapter is a molecular model of phenol that shows its planar structure and electrostatic po- tential. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website As we’ve seen on a number of occasions, bonds to sp 2 -hybridized carbon are shorter than those to sp 3 -hybridized carbon, and the case of phenols is no exception. The carbon–oxygen bond distance in phenol is slightly less than that in methanol. In resonance terms, the shorter carbon–oxygen bond distance in phenol is attrib- uted to the partial double-bond character that results from conjugation of the unshared electron pair of oxygen with the aromatic ring. Many of the properties of phenols reflect the polarization implied by the resonance description. The hydroxyl oxygen is less basic, and the hydroxyl proton more acidic, in phenols than in alcohols. Electrophiles attack the aromatic ring of phenols much faster than they attack benzene, indicating that the ring, especially at the positions ortho and para to the hydroxyl group, is relatively “electron-rich.” 24.3 PHYSICAL PROPERTIES The physical properties of phenols are strongly influenced by the hydroxyl group, which permits phenols to form hydrogen bonds with other phenol molecules (Figure 24.1a) and with water (Figure 24.1b). Thus, phenols have higher melting points and boiling points and are more soluble in water than arenes and aryl halides of comparable molecular weight. Table 24.1 compares phenol, toluene, and fluorobenzene with regard to these physical properties. Some ortho-substituted phenols, such as o-nitrophenol, 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. Dipolar resonance forms of phenol HH HH H OH Most stable Lewis structure for phenol H H11002 H HH H OH H11001 H H11002 H HH H OH H11001 H H11002 H HH H OH H11001 24.3 Physical Properties 941 The physical properties of some representative phenols are collected in Appendix 1. TABLE 24.1 Comparison of Physical Properties of an Arene, a Phenol, and an Aryl Halide Physical property Molecular weight Melting point Boiling point (1 atm) Solubility in water (25°C) Toluene, C 6 H 5 CH 3 92 H1100295°C 111°C 0.05 g/100 mL Phenol, C 6 H 5 OH 94 43°C 132°C 8.2 g/100 mL Fluorobenzene, C 6 H 5 F 96 H1100241°C 85°C 0.2 g/100 mL Compound Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 24.2 One of the hydroxybenzoic acids is known by the common name salicylic acid. Its methyl ester, methyl salicylate, occurs in oil of wintergreen. Methyl salicylate boils over 50°C lower than either of the other two methyl hydroxybenzoates. What is the structure of methyl salicylate? Why is its boiling point so much lower than that of either of its regioisomers? 24.4 ACIDITY OF PHENOLS The most characteristic property of phenols is their acidity. Phenols are more acidic than alcohols but less acidic than carboxylic acids. Recall that carboxylic acids have ioniza- tion constants K a of approximately 10 H110025 (pK a 5), whereas the K a ’s of alcohols are in the 10 H1100216 to 10 H1100220 range (pK a 16–20). The K a for most phenols is about 10 H1100210 (pK a 10). N O O H11002 H O H11001 Intramolecular hydrogen bond in o-nitrophenol 942 CHAPTER TWENTY-FOUR Phenols (a) (b) -------------------- --------------- --------------- FIGURE 24.1 (a) A hy- drogen bond between two phenol molecules; (b) hydro- gen bonds between water and phenol molecules. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website To help us understand why phenols are more acidic than alcohols, let’s compare the ionization equilibria for phenol and ethanol. In particular, consider the differences in charge delocalization in ethoxide ion and in phenoxide ion. The negative charge in ethox- ide ion is localized on oxygen and is stabilized only by solvation forces. The negative charge in phenoxide ion is stabilized both by solvation and by elec- tron delocalization into the ring. Electron delocalization in phenoxide is represented by resonance among the structures: The negative charge in phenoxide ion is shared by the oxygen and the carbons that are ortho and para to it. Delocalization of its negative charge strongly stabilizes phenoxide ion. To place the acidity of phenol in perspective, note that although phenol is more than a million times more acidic than ethanol, it is over a hundred thousand times weaker than acetic acid. Thus, phenols can be separated from alcohols because they are more acidic, and from carboxylic acids because they are less acidic. On shaking an ether solu- tion containing both an alcohol and a phenol with dilute sodium hydroxide, the phenol is converted quantitatively to its sodium salt, which is extracted into the aqueous phase. The alcohol remains in the ether phase. On shaking an ether solution of a phenol and a carboxylic acid with dilute sodium bicar- bonate, the carboxylic acid is converted quantitatively to its sodium salt and extracted into the aqueous phase. The phenol remains in the ether phase. K H11021 1 OH Phenol (weaker acid) H11001 HCO 3 H11002 Bicarbonate ion (weaker base) O H11002 Phenoxide ion (stronger base) H11001 H 2 CO 3 Carbonic acid (stronger acid) K H11022 1 OH Phenol (stronger acid) H11001 HO H11002 Hydroxide ion (stronger base) O H11002 Phenoxide ion (weaker base) H11001 H 2 O Water (weaker acid) HH HH H O H H11002 H HH H O H H11002 H HH H O H H11002 H HH H O H11002 K a H11005 10 H1100210 (pK a H11005 10) Proton H H11001 H11001 Phenol HO Phenoxide ion H11002 O K a H11005 10 H1100216 (pK a H11005 16)HCH 3 CH 2 O Ethanol Proton H H11001 H11001 CH 3 CH 2 O H11002 Ethoxide ion 24.4 Acidity of Phenols 943 Because of its acidity, phenol was known as carbolic acid when Joseph Lister intro- duced it as an antiseptic in 1865 to prevent postopera- tive bacterial infections that were then a life-threatening hazard in even minor surgi- cal procedures. The electrostatic poten- tial map of phenoxide ion on Learning By Modeling displays the delocalization of electrons into the ring. How do we know that water is a weaker acid than phe- nol? What are their respec- tive pK a values? How do we know that car- bonic acid is a stronger acid than phenol? What are their respective pK a values? Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website It is necessary to keep the acidity of phenols in mind when we discuss prepara- tion and reactions. Reactions that produce phenols, when carried out in basic solution, require an acidification step in order to convert the phenoxide ion to the neutral form of the phenol. Many synthetic reactions involving phenols as nucleophiles are carried out in the presence of sodium or potassium hydroxide. Under these conditions the phenol is con- verted to the corresponding phenoxide ion, which is a far better nucleophile. 24.5 SUBSTITUENT EFFECTS ON THE ACIDITY OF PHENOLS As Table 24.2 shows, most phenols have ionization constants similar to that of phenol itself. Substituent effects, in general, are small. Alkyl substitution produces negligible changes in acidities, as do weakly elec- tronegative groups attached to the ring. K H11022 1 OH Phenol (weaker acid) H11001 H 3 O H11001 Hydronium ion (stronger acid) O H11002 Phenoxide ion (stronger base) H11001 H 2 O Water (weaker base) 944 CHAPTER TWENTY-FOUR Phenols How do we know that hy- dronium ion is a stronger acid than phenol? What are their respective pK a values? Recall from Section 24.1 that cresols are methyl- substituted derivatives of phenol. TABLE 24.2 Acidities of Some Phenols Ionization constant K a 1.0 H11003 10 H1100210 4.7 H11003 10 H1100211 8.0 H11003 10 H1100211 5.2 H11003 10 H1100211 2.7 H11003 10 H110029 7.6 H11003 10 H110029 3.9 H11003 10 H110029 1.0 H11003 10 H1100210 2.2 H11003 10 H1100210 6.3 H11003 10 H1100211 5.9 H11003 10 H110028 4.4 H11003 10 H110029 6.9 H11003 10 H110028 1.1 H11003 10 H110024 2.0 H11003 10 H110027 4.2 H11003 10 H110021 5.9 H11003 10 H1100210 3.5 H11003 10 H1100210 pK a 10.0 10.3 10.1 10.3 8.6 9.1 9.4 10.0 9.6 10.2 7.2 8.4 7.2 4.0 6.7 0.4 9.2 9.5 Compound name Monosubstituted phenols Phenol o-Cresol m-Cresol p-Cresol o-Chlorophenol m-Chlorophenol p-Chlorophenol o-Methoxyphenol m-Methoxyphenol p-Methoxyphenol o-Nitrophenol m-Nitrophenol p-Nitrophenol Di- and trinitrophenols 2,4-Dinitrophenol 3,5-Dinitrophenol 2,4,6-Trinitrophenol 1-Naphthol 2-Naphthol Naphthols Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Only when the substituent is strongly electron-withdrawing, as is a nitro group, is a substantial change in acidity noted. The ionization constants of o- and p-nitrophenol are several hundred times greater than that of phenol. An ortho- or para-nitro group greatly stabilizes the phenoxide ion by permitting a portion of the negative charge to be carried by its own oxygens. Electron delocalization in o-nitrophenoxide ion Electron delocalization in p-nitrophenoxide ion A meta-nitro group is not directly conjugated to the phenoxide oxygen and thus stabi- lizes a phenoxide ion to a smaller extent. m-Nitrophenol is more acidic than phenol but less acidic than either o- or p-nitrophenol. PROBLEM 24.3 Which is the stronger acid in each of the following pairs? Explain your reasoning. (a) Phenol or p-hydroxybenzaldehyde (b) m-Cyanophenol or p-cyanophenol (c) o-Fluorophenol or p-fluorophenol SAMPLE SOLUTION (a) The best approach when comparing the acidities of dif- ferent phenols is to assess opportunities for stabilization of negative charge in their anions. Electron delocalization in the anion of p-hydroxybenzaldehyde is very effective because of conjugation with the formyl group. A formyl substituent, like a nitro group, is strongly electron-withdrawing and acid- strengthening, especially when ortho or para to the hydroxyl group. p-Hydroxy- benzaldehyde, with a K a of 2.4 H11003 10 H110028 , is a stronger acid than phenol. Multiple substitution by strongly electron-withdrawing groups greatly increases the acidity of phenols, as the K a values for 2,4-dinitrophenol (K a 1.1 H11003 10 H110024 ) and 2,4,6- trinitrophenol (K a 4.2 H11003 10 H110021 ) in Table 24.2 attest. CHO H11002 O CHO H11002 O O H11002 N H11001 O O H11002 O N H11001 O O H11002H11002 N H11001 O O H11002 O H11002 N H11001 O O H11002 H11002 O 24.5 Substituent Effects on the Acidity of Phenols 945 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.6 SOURCES OF PHENOLS Phenol was first isolated in the early nineteenth century from coal tar, and a small por- tion of the more than 4 billion lb of phenol produced in the United States each year comes from this source. Although significant quantities of phenol are used to prepare aspirin and dyes, most of it is converted to phenolic resins used in adhesives and plas- tics. Almost all the phenol produced commercially is synthetic, with several different processes in current use. These are summarized in Table 24.3. The reaction of benzenesulfonic acid with sodium hydroxide (first entry in Table 24.3) proceeds by the addition–elimination mechanism of nucleophilic aromatic substi- tution (Section 23.6). Hydroxide replaces sulfite ion (SO 3 2H11002 ) at the carbon atom that bears the leaving group. Thus, p-toluenesulfonic acid is converted exclusively to p-cresol by an analogous reaction: PROBLEM 24.4 Write a stepwise mechanism for the conversion of p-toluene- sulfonic acid to p-cresol under the conditions shown in the preceding equation. On the other hand, 14 C-labeling studies have shown that the base-promoted hydrol- ysis of chlorobenzene (second entry in Table 24.3) proceeds by the elimination–addition mechanism and involves benzyne as an intermediate. PROBLEM 24.5 Write a stepwise mechanism for the hydrolysis of chlorobenzene under the conditions shown in Table 24.3. The most widely used industrial synthesis of phenol is based on isopropylbenzene (cumene) as the starting material and is shown in the third entry of Table 24.3. The eco- nomically attractive features of this process are its use of cheap reagents (oxygen and sulfuric acid) and the fact that it yields two high-volume industrial chemicals: phenol and acetone. The mechanism of this novel synthesis forms the basis of Problem 24.29 at the end of this chapter. The most important synthesis of phenols in the laboratory is from amines by hydrolysis of their corresponding diazonium salts, as described in Section 22.18: 24.7 NATURALLY OCCURRING PHENOLS Phenolic compounds are commonplace natural products. Figure 24.2 presents a sampling of some naturally occurring phenols. Phenolic natural products can arise by a number of different biosynthetic pathways. In mammals, aromatic rings are hydroxylated by way 1. NaNO 2 , H 2 SO 4 H 2 O 2. H 2 O, heat NO 2 H 2 N m-Nitroaniline HO NO 2 m-Nitrophenol (81–86%) SO 3 H CH 3 p-Toluenesulfonic acid OH CH 3 p-Cresol (63–72%) 1. KOH–NaOH mixture, 330°C 2. H H11001 946 CHAPTER TWENTY-FOUR Phenols Can you recall how to pre- pare p-toluenesulfonic acid? Can you recall how to pre- pare chlorobenzene? Can you recall how to pre- pare isopropylbenzene? Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.7 Naturally Occurring Phenols 947 TABLE 24.3 Industrial Syntheses of Phenol Reaction and comments Reaction of benzenesulfonic acid with sodium hydroxide This is the oldest method for the prepa- ration of phenol. Benzene is sulfonated and the benzenesulfonic acid heated with molten sodium hydroxide. Acidification of the reaction mixture gives phenol. Hydrolysis of chlorobenzene Heating chloroben- zene with aqueous sodium hydroxide at high pres- sure gives phenol after acidification. From cumene Almost all the phenol produced in the United States is prepared by this method. Oxi- dation of cumene takes place at the benzylic posi- tion to give a hydroperoxide. On treatment with dilute sulfuric acid, this hydroperoxide is converted to phenol and acetone. Chemical equation 1. NaOH 300–350°C 2. H H11001 SO 3 H Benzenesulfonic acid OH Phenol 1. NaOH, H 2 O 370°C 2. H H11001 OH Phenol Cl Chlorobenzene O 2 CH(CH 3 ) 2 Isopropylbenzene (cumene) C(CH 3 ) 2 OOH 1-Methyl-1-phenylethyl hydroperoxide H11001 Acetone (CH 3 ) 2 COOH Phenol C(CH 3 ) 2 OOH 1-Methyl-1-phenylethyl hydroperoxide H 2 O H 2 SO 4 CH(CH 3 ) 2 (CH 2 ) 4 CH 3 CH(CH 3 ) 2 CH(CH 3 ) 2 CH 3 CH 3 CH 3 CH 3 OH Thymol (major constituent of oil of thyme) Cl Cl OH 2,5-Dichlorophenol (isolated from defensive secretion of a species of grasshopper) O H9004 9 -Tetrahydrocannabinol (active component of marijuana) OHHC OH OH O HC O HO HO HO HO CH 3 CH 3 Gossypol (About 10 9 lb of this material is obtained each year in the United States as a byproduct of cotton-oil production.) FIGURE 24.2 Some naturally occurring phenols. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website of arene oxide intermediates formed by the enzyme-catalyzed reaction between an aro- matic ring and molecular oxygen: In plants, phenol biosynthesis proceeds by building the aromatic ring from carbohydrate precursors that already contain the required hydroxyl group. 24.8 REACTIONS OF PHENOLS: ELECTROPHILIC AROMATIC SUBSTITUTION In most of their reactions phenols behave as nucleophiles, and the reagents that act on them are electrophiles. Either the hydroxyl oxygen or the aromatic ring may be the site of nucleophilic reactivity in a phenol. Reactions that take place on the ring lead to elec- trophilic aromatic substitution; Table 24.4 (p. 950) summarizes the behavior of phenols in reactions of this type. A hydroxyl group is a very powerful activating substituent, and electrophilic aro- matic substitution in phenols occurs far faster, and under milder conditions, than in ben- zene. The first entry in Table 24.4, for example, shows the monobromination of phenol in high yield at low temperature and in the absence of any catalyst. In this case, the reac- tion was carried out in the nonpolar solvent 1,2-dichloroethane. In polar solvents such as water it is difficult to limit the bromination of phenols to monosubstitution. In the fol- lowing example, all three positions that are ortho or para to the hydroxyl undergo rapid substitution: Other typical electrophilic aromatic substitution reactions—nitration (second entry), sul- fonation (fourth entry), and Friedel–Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo elec- trophilic substitution reactions that are limited to only the most active aromatic com- pounds; these include nitrosation (third entry) and coupling with diazonium salts (sev- enth entry). PROBLEM 24.6 Each of the following reactions has been reported in the chem- ical literature and gives a single organic product in high yield. Identify the prod- uct in each case. (a) 3-Benzyl-2,6-dimethylphenol treated with bromine in chloroform (b) 4-Bromo-2-methylphenol treated with 2-methylpropene and sulfuric acid (c) 2-Isopropyl-5-methylphenol (thymol) treated with sodium nitrite and dilute hydrochloric acid (d) p-Cresol treated with propanoyl chloride and aluminum chloride H 2 O 25°C OH F m-Fluorophenol H11001 3Br 2 Bromine Br OH F Br Br 2,4,6-Tribromo-3- fluorophenol (95%) H11001 3HBr Hydrogen bromide enzyme R Arene H11001 O 2 R O Arene oxide HO R Phenol 948 CHAPTER TWENTY-FOUR Phenols Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website SAMPLE SOLUTION (a) The ring that bears the hydroxyl group is much more reactive than the other ring. In electrophilic aromatic substitution reactions of rings that bear several substituents, it is the most activating substituent that con- trols the orientation. Bromination occurs para to the hydroxyl group. The aromatic ring of a phenol, like that of an arylamine, is seen as an electron- rich functional unit and is capable of a variety of reactions. In some cases, however, it is the hydroxyl oxygen that reacts instead. An example of this kind of chemical reac- tivity is described in the following section. 24.9 ACYLATION OF PHENOLS Acylating agents, such as acyl chlorides and carboxylic acid anhydrides, can react with phenols either at the aromatic ring (C-acylation) or at the hydroxyl oxygen (O-acyla- tion): As shown in the sixth entry of Table 24.4, C-acylation of phenols is observed under the customary conditions of the Friedel–Crafts reaction (treatment with an acyl chloride or acid anhydride in the presence of aluminum chloride). In the absence of aluminum chloride, however, O-acylation occurs instead. The O-acylation of phenols with carboxylic acid anhydrides can be conveniently catalyzed in either of two ways. One method involves converting the acid anhydride to a more powerful acylating agent by protonation of one of its carbonyl oxygens. Addi- tion of a few drops of sulfuric acid is usually sufficient. OHF p-Fluorophenol CH 3 COCCH 3 O O Acetic anhydride CH 3 COH O Acetic acid H11001H11001F OCCH 3 O p-Fluorophenyl acetate (81%) H 2 SO 4 OH Phenol CH 3 (CH 2 ) 6 CCl O Octanoyl chloride HCl Hydrogen chloride H11001H11001OC(CH 2 ) 6 CH 3 O Phenyl octanoate (95%) RCCl or RCOCR O X O X O X OH Phenol RC O OH Aryl ketone (product of C-acylation) or OCR O Aryl ester (product of O-acylation) Br 2 CHCl 3 , 0°C CH 2 H 3 C CH 3 OH 3-Benzyl-2,6-dimethylphenol H 3 C CH 3 CH 2 OH Br 3-Benzyl-4-bromo-2,6-dimethylphenol (isolated in 100% yield) 24.9 Acylation of Phenols 949 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 950 CHAPTER TWENTY-FOUR Phenols TABLE 24.4 Electrophilic Aromatic Substitution Reactions of Phenols Reaction and comments Halogenation Bromination and chlorination of phe- nols occur readily even in the absence of a catalyst. Substitution occurs primarily at the position para to the hydroxyl group. When the para position is blocked, ortho substitution is observed. Nitration Phenols are nitrated on treatment with a dilute solution of nitric acid in either water or acetic acid. It is not necessary to use mixtures of nitric and sulfuric acids, because of the high reactivity of phe- nols. Nitrosation On acidification of aqueous solutions of sodium nitrite, the nitrosonium ion ( : NPO H11001 : ) is formed, which is a weak electrophile and attacks the strongly activated ring of a phenol. The product is a nitroso phenol. Sulfonation Heating a phenol with concentrated sulfuric acid causes sulfonation of the ring. Friedel-Crafts alkylation Alcohols in combination with acids serve as sources of carbocations. Attack of a carbocation on the electron-rich ring of a phe- nol brings about its alkylation. (Continued) Specific example OH Phenol OH Br p-Bromophenol (93%) ClCH 2 CH 2 Cl 0°C H11001 Br 2 Bromine H11001 HBr Hydrogen bromide OH CH 3 p-Cresol OH NO 2 CH 3 4-Methyl-2-nitrophenol (73–77%) HNO 3 acetic acid 5°C OH CH 3 H 3 C 2,6-Dimethylphenol OH CH 3 SO 3 H H 3 C 4-Hydroxy-3,5- dimethylbenzenesulfonic acid (69%) H 2 SO 4 100°C OH 2-Naphthol 1-Nitroso-2-naphthol (99%) NO OH NaNO 2 H 2 SO 4 , H 2 O 0°C OH CH 3 o-Cresol OH CH 3 C(CH 3 ) 3 4-tert-Butyl-2- methylphenol (63%) H 3 PO 4 60°C H11001 (CH 3 ) 3 COH tert-Butyl alcohol Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website An alternative approach is to increase the nucleophilicity of the phenol by con- verting it to its phenoxide anion in basic solution: PROBLEM 24.7 Write chemical equations expressing each of the following: (a) Preparation of o-nitrophenyl acetate by sulfuric acid catalysis of the reac- tion between a phenol and a carboxylic acid anhydride. (b) Esterification of 2-naphthol with acetic anhydride in aqueous sodium hydroxide (c) Reaction of phenol with benzoyl chloride SAMPLE SOLUTION (a) The problem specifies that an acid anhydride be used; therefore, use acetic anhydride to prepare the acetate ester of o-nitrophenol: OH NO 2 o-Nitrophenol H11001 CH 3 COCCH 3 OO Acetic anhydride H 2 SO 4 OCCH 3 O NO 2 o-Nitrophenyl acetate (isolated in 93% yield by this method) H11001 CH 3 COH O Acetic acid HO OH Resorcinol 2CH 3 COCCH 3 O O Acetic anhydride 2CH 3 CONa O Sodium acetate H11001H11001 NaOH H 2 O OCCH 3 O CH 3 CO O 1,3-Diacetoxybenzene (93%) 24.9 Acylation of Phenols 951 TABLE 24.4 Electrophilic Aromatic Substitution Reactions of Phenols (Continued) Reaction and comments Friedel-Crafts acylation In the presence of alumi- num chloride, acyl chlorides and carboxylic acid anhydrides acylate the aromatic ring of phenols. Reaction with arenediazonium salts Adding a phe- nol to a solution of a diazonium salt formed from a primary aromatic amine leads to formation of an azo compound. The reaction is carried out at a pH such that a significant portion of the phenol is pres- ent as its phenoxide ion. The diazonium ion acts as an electrophile toward the strongly activated ring of the phenoxide ion. Specific example OH 2-Naphthol 1-Phenylazo-2-naphthol (48%) NNC 6 H 5 OH C 6 H 5 NPN Cl H11002 H11001 OH CCH 3 O o-Hydroxyaceto- phenone (16%) OH Phenol CH 3 CCl AlCl 3 O X H11001 p-Hydroxyaceto- phenone (74%) OH C OH 3 C Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The preference for O-acylation of phenols arises because these reactions are kinet- ically controlled. O-acylation is faster than C-acylation. The C-acyl isomers are more stable, however, and it is known that aluminum chloride is a very effective catalyst for the conversion of aryl esters to aryl ketones. (This isomerization is called the Fries rearrangement.) Thus, ring acylation of phenols is observed under Friedel–Crafts conditions because the presence of aluminum chloride causes that reaction to be subject to thermodynamic (equi- librium) control. Fischer esterification, in which a phenol and a carboxylic acid condense in the pres- ence of an acid catalyst, is not used to prepare aryl esters. 24.10 CARBOXYLATION OF PHENOLS: ASPIRIN AND THE KOLBE–SCHMITT REACTION The best known aryl ester is O-acetylsalicylic acid, better known as aspirin. It is pre- pared by acetylation of the phenolic hydroxyl group of salicylic acid: Aspirin possesses a number of properties that make it an often-recommended drug. It is an analgesic, effective in relieving headache pain. It is also an antiinflammatory agent, providing some relief from the swelling associated with arthritis and minor injuries. Aspirin is an antipyretic compound; that is, it reduces fever. Each year, more than 40 million lb of aspirin is produced in the United States, a rate equal to 300 tablets per year for every man, woman, and child. The key compound in the synthesis of aspirin, salicylic acid, is prepared from phe- nol by a process discovered in the nineteenth century by the German chemist Hermann Kolbe. In the Kolbe synthesis, also known as the Kolbe–Schmitt reaction, sodium phen- oxide is heated with carbon dioxide under pressure, and the reaction mixture is subse- quently acidified to yield salicylic acid: ONa Sodium phenoxide CO 2 Na OH Sodium salicylate CO 2 125°C, 100 atm CO 2 H OH Salicylic acid (79%) H H11001 OH CO 2 H Salicylic acid (o-hydroxybenzoic acid) CO 2 H OCCH 3 O O-Acetylsalicylic acid (aspirin) CH 3 COCCH 3 O O Acetic anhydride CH 3 COH O Acetic acid H11001H11001 H 2 SO 4 AlCl 3 OH CC 6 H 5 O o-Hydroxybenzophenone (9%) OHC 6 H 5 C O p-Hydroxybenzophenone (64%) H11001OCC 6 H 5 O Phenyl benzoate 952 CHAPTER TWENTY-FOUR Phenols An entertaining account of the history of aspirin can be found in the 1991 book The Aspirin Wars: Money, Medi- cine, and 100 Years of Ram- pant Competition, by Charles C. Mann. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Although a hydroxyl group strongly activates an aromatic ring toward electrophilic attack, an oxyanion substituent is an even more powerful activator. Electron delocaliza- tion in phenoxide anion leads to increased electron density at the positions ortho and para to oxygen. The increased nucleophilicity of the ring permits it to react with carbon dioxide. An inter- mediate is formed that is simply the keto form of salicylate anion: The Kolbe–Schmitt reaction is an equilibrium process governed by thermodynamic control. The position of equilibrium favors formation of the weaker base (salicylate ion) at the expense of the stronger one (phenoxide ion). Thermodynamic control is also responsible for the pronounced bias toward ortho over para substitution. Salicylate anion is a weaker base than p-hydroxybenzoate and so is the predominant species at equilib- rium. Salicylate anion is a weaker base than p-hydroxybenzoate because it is stabilized by intramolecular hydrogen bonding. The Kolbe–Schmitt reaction has been applied to the preparation of other o-hydroxy- benzoic acids. Alkyl derivatives of phenol behave very much like phenol itself. Intramolecular hydrogen bonding in salicylate anion O C H O O H11002 rather than O H11002 Phenoxide ion (strongest base; K a of conjugate acid, 10 H1100210 ) H11001 CO 2 Carbon dioxide OH CO 2 H11002 Salicylate anion (weakest base; K a of conjugate acid, 1.06 H11003 10 H110023 ) OH H11002 O 2 C p-Hydroxybenzoate anion (K a of conjugate acid, 3.3 H11003 10 H110025 ) H O H11002 Phenoxide anion (stronger base) C O O Carbon dioxide H C O O O H11002 Cyclohexadienone intermediate OH C O O H11002 Salicylate anion (weaker base) HH HH H O H H11002 H HH H O H H11002 H HH H O H H11002 H HH H O H11002 24.10 Carboxylation of Phenols: Aspirin and the Kolbe–Schmitt Reaction 953 This is the same resonance description shown in Section 24.4. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Phenols that bear strongly electron-withdrawing substituents usually give low yields of carboxylated products; their derived phenoxide anions are less basic, and the equilibrium constants for their carboxylation are smaller. 24.11 PREPARATION OF ARYL ETHERS Aryl ethers are best prepared by the Williamson method (Section 16.6). Alkylation of the hydroxyl oxygen of a phenol takes place readily when a phenoxide anion reacts with an alkyl halide. As the synthesis is normally performed, a solution of the phenol and alkyl halide is simply heated in the presence of a suitable base such as potassium carbonate: The alkyl halide must be one that reacts readily in an S N 2 process. Thus, methyl and primary alkyl halides are the most effective alkylating agents. Elimination becomes competitive with substitution when secondary alkyl halides are used and is the only reac- tion observed with tertiary alkyl halides. PROBLEM 24.8 Reaction of phenol with 1,2-epoxypropane in aqueous sodium hydroxide at 150°C gives a single product, C 9 H 12 O 2 , in 90% yield. Suggest a rea- sonable structure for this compound. The reaction between an alkoxide ion and an aryl halide can be used to prepare alkyl aryl ethers only when the aryl halide is one that reacts rapidly by the addition–elim- ination mechanism of nucleophilic aromatic substitution (Section 23.6). K 2 CO 3 acetone heat OH Phenol H11001 CH 2 CHCH 2 Br Allyl bromide OCH 2 CH CH 2 Allyl phenyl ether (86%) acetone heat ONa Sodium phenoxide H11001 CH 3 I Iodomethane OCH 3 Anisole (95%) H11001 NaI Sodium iodide S N 2 ArO H11002 Phenoxide anion H11001 RX Alkyl halide ArOR Alkyl aryl ether H11001 H11002 X Halide anion 1. NaOH 2. CO 2 , 125°C, 100 atm 3. H H11001 OH CH 3 p-Cresol OH CH 3 CO 2 H 2-Hydroxy-5-methylbenzoic acid (78%) 954 CHAPTER TWENTY-FOUR Phenols This is an example of an S N 2 reaction in a polar aprotic solvent. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.11 Preparation of Aryl Ethers 955 AGENT ORANGE AND DIOXIN T he once widely used herbicide 2,4,5- trichlorophenoxyacetic acid (2,4,5-T) is prepared by reaction of the sodium salt of 2,4,5-trichlorophe- nol with chloroacetic acid: The starting material for this process, 2,4,5- trichlorophenol, is made by treating 1,2,4,5-tetra- chlorobenzene with aqueous base. Nucleophilic aro- matic substitution of one of the chlorines by an addition–elimination mechanism yields 2,4,5- trichlorophenol: Dioxin is carried along when 2,4,5-trichlorophe- nol is converted to 2,4,5-T, and enters the environ- ment when 2,4,5-T is sprayed on vegetation. Typi- cally, the amount of dioxin present in 2,4,5-T is very small. Agent Orange, a 2,4,5-T–based defoliant used on a large scale in the Vietnam War, contained about 2 ppm of dioxin. Tests with animals have revealed that dioxin is one of the most toxic substances known. Toward mice it is about 2000 times more toxic than strychnine and about 150,000 times more toxic than sodium cyanide. Fortunately, however, available evidence indicates that humans are far more resistant to dioxin than are test animals, and so far there have been no human fatalities directly attributable to dioxin. The most prominent short-term symptom seen so far has been a severe skin disorder known as chloracne. Yet to be determined is the answer to the question of long- term effects. A 1991 study of the health records of over 5000 workers who were exposed to dioxin- contaminated chemicals indicated a 15% increase in incidences of cancer compared with those of a control group. Workers who were exposed to higher dioxin levels for prolonged periods exhibited a 50% increase in their risk of dying from cancer, especially soft-tissue sarcomas, compared with the control group.* Since 1979, the use of 2,4,5-T has been regu- lated in the United States. In the course of making 2,4,5-trichlorophenol, it almost always becomes contaminated with small amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin, bet- ter known as dioxin. ONa ClCl Cl Sodium 2,4,5-trichlorophenolate H11001 ClCH 2 CO 2 H Chloroacetic acid OCH 2 CO 2 H ClCl Cl 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) H11001 NaCl ClO Cl Cl Cl O 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin) ClCl Cl Cl 1,2,4,5-Tetrachlorobenzene ClCl Cl OH 2,4,5-Trichlorophenol 1. NaOH, H 2 O 2. H H11001 * The biological properties of dioxin include an ability to bind to a protein known as the AH (aromatic hydrocarbon) receptor. Dioxin is not a hydrocarbon, but it shares a certain structural property with aromatic hydrocarbons. Try constructing molecular models of dioxin and anthracene to see these similarities. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website PROBLEM 24.9 Which of the following two combinations of reactants is more appropriate for the preparation of p-nitrophenyl phenyl ether? (a) Fluorobenzene and p-nitrophenol (b) p-Fluoronitrobenzene and phenol 24.12 CLEAVAGE OF ARYL ETHERS BY HYDROGEN HALIDES The cleavage of dialkyl ethers by hydrogen halides was discussed in Section 16.8, where it was noted that the same pair of alkyl halides results, irrespective of the order in which the carbon–oxygen bonds of the ether are broken. Cleavage of alkyl aryl ethers by hydrogen halides always proceeds so that the alkyl–oxygen bond is broken and yields an alkyl halide and a phenol as the final prod- ucts. Since phenols are not converted to aryl halides by reaction with hydrogen halides, reac- tion proceeds no further than shown in the preceding general equation. For example, The first step in the reaction of an alkyl aryl ether with a hydrogen halide is pro- tonation of oxygen to form an alkylaryloxonium ion: H11001 fast R ArO Alkyl aryl ether HX Hydrogen halide ArO R H H11001 Alkylaryloxonium ion H11001 H11002 X Halide ion OCH 3 OH Guaiacol HBr heat OH OH Pyrocatechol (85–87%) H11001 CH 3 Br Methyl bromide (57–72%) H11001H11001ArOR Alkyl aryl ether HX Hydrogen halide RX Alkyl halide Phenol ArOH H11001H11001RORH11032 Dialkyl ether 2HX Hydrogen halide H 2 O WaterTwo alkyl halides H11001RX RH11032X F NO 2 p-Fluoronitrobenzene OCH 3 NO 2 p-Nitroanisole (93%) KOCH 3 CH 3 OH, 25°C 956 CHAPTER TWENTY-FOUR Phenols Guaiacol is obtained by chemical treatment of lignum vitae, the wood from a species of tree that grows in warm climates. It is some- times used as an expectorant to help relieve bronchial con- gestion. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website This is followed by a nucleophilic substitution step: Attack by the halide nucleophile at the sp 3 -hybridized carbon of the alkyl group is anal- ogous to what takes place in the cleavage of dialkyl ethers. Attack at the sp 2 -hybridized carbon of the aromatic ring is much slower. Indeed, nucleophilic aromatic substitution does not occur at all under these conditions. 24.13 CLAISEN REARRANGEMENT OF ALLYL ARYL ETHERS Allyl aryl ethers undergo an interesting reaction, called the Claisen rearrangement, on being heated. The allyl group migrates from oxygen to the ring carbon ortho to it. Carbon-14 labeling of the allyl group revealed that the terminal carbon of the allyl group is the one that becomes bonded to the ring and suggests a mechanism involving a con- certed electron reorganization in the first step. This step is followed by enolization of the resulting cyclohexadienone to regenerate the aromatic ring. PROBLEM 24.10 The mechanism of the Claisen rearrangement of other allylic ethers of phenol is analogous to that of allyl phenyl ether. What is the product of the Claisen rearrangement of C 6 H 5 OCH 2 CH?CHCH 3 ? The transition state for the first step of the Claisen rearrangement bears much in common with the transition state for the Diels–Alder cycloaddition. Both involve a con- certed six-electron reorganization. via O via O Claisen rearrangement Diels–Alder cycloaddition rearrangement enolization * H11005 14 C O * Allyl phenyl ether * O H 6-Allyl-2,4-cyclohexadienone * OH o-Allylphenol 200°C OCH 2 CH CH 2 Allyl phenyl ether OH CH 2 CH CH 2 o-Allylphenol (73%) H11001 slow RX Alkyl halide ArO R H H11001 Alkylaryloxonium ion H11001 H11002 X Halide ion ArO H Phenol 24.13 Claisen Rearrangement of Allyl Aryl Ethers 957 Allyl phenyl ether is prepared by the reaction of phenol with allyl bromide, as de- scribed in Section 24.11 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The Claisen rearrangement is an example of a sigmatropic rearrangement. A sigma- tropic rearrangement is characterized by a transition state in which a H9268 bond migrates from one end of a conjugated H9266 electron system to the other. In this case the H9268 bond to oxygen at one end of an allyl unit is broken and replaced by a H9268 bond to the ring car- bon at the other end. 24.14 OXIDATION OF PHENOLS: QUINONES Phenols are more easily oxidized than alcohols, and a large number of inorganic oxi- dizing agents have been used for this purpose. The phenol oxidations that are of the most use to the organic chemist are those involving derivatives of 1,2-benzenediol (pyrocate- chol) and 1,4-benzenediol (hydroquinone). Oxidation of compounds of this type with silver oxide or with chromic acid yields conjugated dicarbonyl compounds called quinones. Quinones are colored; p-benzoquinone, for example, is yellow. Many occur natu- rally and have been used as dyes. Alizarin is a red pigment extracted from the roots of the madder plant. Its preparation from anthracene, a coal tar derivative, in 1868 was a significant step in the development of the synthetic dyestuff industry. The oxidation–reduction process that connects hydroquinone and benzoquinone involves two 1-electron transfers: O O OH OH Alizarin OH OH Hydroquinone O O p-Benzoquinone (76–81%) Na 2 Cr 2 O 7 H 2 SO 4 , H 2 O Ag 2 O ether OH OH CH 3 4-Methylpyrocatechol (4-methyl-1,2-benzenediol) O O CH 3 4-Methyl-1,2-benzoquinone (68%) 958 CHAPTER TWENTY-FOUR Phenols Silver oxide is a weak oxidiz- ing agent. Quinones that are based on the anthracene ring system are called anthraquinones. Alizarin is one example of an anthraquinone dye. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The ready reversibility of this reaction is essential to the role that quinones play in cellular respiration, the process by which an organism uses molecular oxygen to convert its food to carbon dioxide, water, and energy. Electrons are not transferred directly from the substrate molecule to oxygen but instead are transferred by way of an electron trans- port chain involving a succession of oxidation–reduction reactions. A key component of this electron transport chain is the substance known as ubiquinone, or coenzyme Q: The name ubiquinone is a shortened form of ubiquitous quinone, a term coined to describe the observation that this substance can be found in all cells. The length of its side chain varies among different organisms; the most common form in vertebrates has n H11005 10, and ubiquinones in which n H11005 6 to 9 are found in yeasts and plants. Another physiologically important quinone is vitamin K. Here “K” stands for koag- ulation (Danish), since this substance was first identified as essential for the normal clot- ting of blood. Some vitamin K is provided in the normal diet, but a large proportion of that required by humans is produced by their intestinal flora. CH 2 CH O O CH 3 CH 3 CH 3 CCH 2 (CH 2 CH 2 CHCH 2 ) 3 H Vitamin K n H11005 6–10 O O CH 3 (CH 2 CH CH 3 O CH 3 O CH 3 CCH 2 ) n H Ubiquinone (coenzyme Q) OH OH Hydroquinone O OH H11001 H H11001 e H11002 H11001 O OH O O Benzoquinone H11001 H H11001 H11001 e H11002 24.14 Oxidation of Phenols: Quinones 959 “Intestinal flora” is a general term for the bacteria, yeast, and fungi that live in the large intestine. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.15 SPECTROSCOPIC ANALYSIS OF PHENOLS Infrared: The infrared spectra of phenols combine features of those of alcohols and aromatic compounds. Hydroxyl absorbances resulting from O±H stretching are found in the 3600-cm H110021 region, and the peak due to C±O stretching appears around 1200–1250 cm H110021 . These features can be seen in the infrared spectrum of p-cresol, shown in Figure 24.3. 1 H NMR: The 1 H NMR signals for the hydroxyl protons of phenols are often broad, and their chemical shift, like their acidity, lies between alcohols and carboxylic acids. The range is H9254 4–12 ppm, with the exact chemical shift depending on the concentration, the solvent, and the temperature. The phenolic proton in the 1 H NMR spectrum shown for p-cresol, for example, appears at H9254 5.1 ppm (Figure 24.4). 13 C NMR: Compared with C±H, the carbon of C±O in a phenol is deshielded by about 25 ppm. In the case of m-cresol, for example, the C±O carbon gives the signal at lowest field. 13 C chemical shifts H9254 in m-cresol (ppm) CH 3 OH 112.3 116.1 129.4 139.8 155.1 121.7 21.3 960 CHAPTER TWENTY-FOUR Phenols Wave number, cm H110021 Wavelength, H9262m Transmittance (%) C±O OH W CH 3 W OH FIGURE 24.3 The in- frared spectrum of p-cresol. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.15 Spectroscopic Analysis of Phenols 961 0.01.02.03.04.0 Chemical shift (δ, ppm) 6.07.08.09.010.0 5.0 6.8 6.76.97.07.1 H W CH 3 CH 3 W OH ± H± H± H± FIGURE 24.4 The 200-MHz 1 H NMR spectrum of p-cresol. The 13 C NMR spectrum of m-cresol appeared in Chap- ter 13 (Figure 13.21). Notice, too, that the most shielded carbons of the aromatic ring are the ones that are ortho and para to the hydroxyl group in keeping with our experience that the OH group donates electrons preferentially to these positions. UV-VIS: Just as with arylamines (Section 22.20), it is informative to look at the UV-VIS behavior of phenols in terms of how the OH group affects the benzene chromophore. An OH group affects the UV-VIS spectrum of benzene in a way similar to that of an NH 2 group, but to a smaller extent. In basic solution, in which OH is converted to O H11002 , however, the shift to longer wavelengths exceeds that of an NH 2 group. Mass Spectrometry: A peak for the molecular ion is usually quite prominent in the mass spectra of phenols. It is, for example, the most intense peak in phenol. X Benzene Aniline Anilinium ion Phenol Phenoxide ion X H NH 2 NH 3 H11001 OH O H11002 204, 256 230, 280 203, 254 210, 270 235, 287 H9261 max , nm Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.16 SUMMARY Section 24.1 Phenol is both an important industrial chemical and the parent of a large class of compounds widely distributed as natural products. Although ben- zenol is the systematic name for C 6 H 5 OH, the IUPAC rules permit phe- nol to be used instead. Substituted derivatives are named on the basis of phenol as the parent compound. Section 24.2 Phenols are polar compounds, but less polar than alcohols. They resem- ble arylamines in having an electron-rich aromatic ring. Section 24.3 The ±OH group of phenols makes it possible for them to participate in hydrogen bonding. This contributes to the higher boiling points and greater water-solubility of phenolic compounds compared with arenes and aryl halides. Section 24.4 With K a ’s of approximately 10 H1100210 (pK a H11005 10), phenols are stronger acids than alcohols, but weaker than carboxylic acids. They are converted quan- titatively to phenoxide anions on treatment with aqueous sodium hydrox- ide. ArOH H11001 NaOH ±￡ ArONa H11001 H 2 O Section 24.5 Electron-releasing substituents attached to the ring have a negligible effect on the acidity of phenols. Strongly electron-withdrawing groups increase the acidity. The compound 4-nitro-3-(trifluoromethyl)phenol, for example, is 10,000 times more acidic than phenol. Section 24.6 Table 24.3 listed the main industrial methods for the preparation of phe- nol. Laboratory syntheses of phenols is usually carried out by hydrolysis of aryl diazonium salts. 1. NaNO 2 , H 2 SO 4 , H 2 O 2. H 2 O, heat F CH 3 ONH 2 3-Fluoro-4-methoxyaniline F CH 3 O OH 3-Fluoro-4-methoxyphenol (70%) ArNH 2 Arylamine ArOH A phenol NaNO 2 , H H11001 H 2 O heat Aryl diazonium ion ArN N H11001 4-Nitro-3-(trifluoromethyl)phenol: pK a H11005 6.0 CF 3 OH NO 2 962 CHAPTER TWENTY-FOUR Phenols Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Section 24.7 Many phenols occur naturally. Phenol biosynthesis in plants proceeds from carbohydrate precursors, whereas the pathway in animals involves oxidation of aromatic rings. Section 24.8 The hydroxyl group of a phenol is a strongly activating substituent, and electrophilic aromatic substitution occurs readily in phenol and its deriv- atives. Typical examples were presented in Table 24.4. Section 24.9 On reaction with acyl chlorides and acid anhydrides, phenols may undergo either acylation of the hydroxyl group (O-acylation) or acylation of the ring (C-acylation). The product of C-acylation is more stable and predominates under conditions of thermodynamic control when alu- minum chloride is present (see entry 6 in Table 24.4, Section 24.8). O-acylation is faster than C-acylation, and aryl esters are formed under conditions of kinetic control. Section 24.10 The Kolbe–Schmitt synthesis of salicylic acid is a vital step in the prepa- ration of aspirin. Phenols, as their sodium salts, undergo highly regiose- lective ortho carboxylation on treatment with carbon dioxide at elevated temperature and pressure. C(CH 3 ) 3 ONa Sodium p-tert-butylphenoxide OH C(CH 3 ) 3 CO 2 H 5-tert-Butyl-2- hydroxybenzoic acid (74%) 1. CO 2 , heat, pressure 2. H H11001 CH 3 COCCH 3 H 2 SO 4 O X O X OH NO 2 o-Nitrophenol OCCH 3 NO 2 O o-Nitrophenyl acetate (93%) RCX O Acylating agent Aryl ester ArOCR O HXH11001H11001ArOH A phenol Zingerone (responsible for spicy taste of ginger) HO CH 3 O CH 2 CH 2 CCH 3 O 24.16 Summary 963 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Section 24.11 Phenoxide anions are nucleophilic toward alkyl halides, and the prepara- tion of alkyl aryl ethers is easily achieved under S N 2 conditions. Section 24.12 The cleavage of alkyl aryl ethers by hydrogen halides yields a phenol and an alkyl halide. Section 24.13 On being heated, allyl aryl ethers undergo a Claisen rearrangement to form o-allylphenols. A cyclohexadienone, formed by a concerted six-H9266- electron reorganization, is an intermediate. Section 24.14 Oxidation of 1,2- and 1,4-benzenediols gives colored compounds known as quinones. Section 24.15 The infrared and 1 H NMR spectra of phenols are similar to those for alco- hols, except that the OH proton is somewhat less shielded in a phenol than in an alcohol. In 13 C NMR, an OH group deshields the carbon of Ag 2 O ether CH 3 OHH 3 C OHH 3 C CH 3 3,4,5,6-Tetramethyl-1,2- benzenediol H 3 C H 3 C CH 3 CH 3 O O 3,4,5,6-Tetramethyl-1,2- benzoquinone (81%) HX Hydrogen halide A phenol ArOH heat RX Alkyl halide H11001H11001ArOR Alkyl aryl ether HI heat CH 2 CO 2 H CH 3 O m-Methoxyphenylacetic acid CH 2 CO 2 H HO m-Hydroxyphenylacetic acid (72%) H11001 CH 3 I Methyl iodide CH 3 CH 2 CH 2 CH 2 Br K 2 CO 3 NO 2 OH o-Nitrophenol NO 2 OCH 2 CH 2 CH 2 CH 3 Butyl o-nitrophenyl ether (75/80%) RX Alkyl halide Alkyl aryl ether ArOR X H11002 Halide anion H11001H11001ArO H11002 Phenoxide anion 964 CHAPTER TWENTY-FOUR Phenols 200°C OCH 2 CH Br CH 2 Allyl o-bromophenyl ether OH Br CH 2 CH CH 2 2-Allyl-6-bromophenol (82%) via O Br H CH 2 CH CH 2 6-Allyl-2-bromo- 2,4-cyclohexadienone Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website an aromatic ring to which it is attached. An OH group causes a shift in the UV-VIS spectrum of benzene to longer wavelengths. The effect is quite large in basic solution because of conversion of OH to O H11002 . PROBLEMS 24.11 The IUPAC rules permit the use of common names for a number of familiar phenols and aryl ethers. These common names are listed here along with their systematic names. Write the structure of each compound. (a) Vanillin (4-hydroxy-3-methoxybenzaldehyde): a component of vanilla bean oil, which contributes to its characteristic flavor (b) Thymol (2-isopropyl-5-methylphenol): obtained from oil of thyme (c) Carvacrol (5-isopropyl-2-methylphenol): present in oil of thyme and marjoram (d) Eugenol (4-allyl-2-methoxyphenol): obtained from oil of cloves (e) Gallic acid (3,4,5-trihydroxybenzoic acid): prepared by hydrolysis of tannins derived from plants (f) Salicyl alcohol (o-hydroxybenzyl alcohol): obtained from bark of poplar and willow trees 24.12 Name each of the following compounds: (a) (d) (b) (e) (c) 24.13 Write a balanced chemical equation for each of the following reactions: (a) Phenol H11001 sodium hydroxide (b) Product of part (a) H11001 ethyl bromide (c) Product of part (a) H11001 butyl p-toluenesulfonate (d) Product of part (a) H11001 acetic anhydride (e) o-Cresol H11001 benzoyl chloride (f) m-Cresol H11001 ethylene oxide (g) 2,6-Dichlorophenol H11001 bromine (h) p-Cresol H11001 excess aqueous bromine (i) Isopropyl phenyl ether H11001 excess hydrogen bromide H11001 heat CH 2 Cl HO Cl OCCCl 3 Cl O CH 2 CH 3 NO 2 OH H 3 C CH(CH 3 ) 2 OCH 3 CH 3 CH 2 CH 3 NO 2 OH Problems 965 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.14 Which phenol in each of the following pairs is more acidic? Justify your choice. (a) 2,4,6-Trimethylphenol or 2,4,6-trinitrophenol (b) 2,6-Dichlorophenol or 3,5-dichlorophenol (c) 3-Nitrophenol or 4-nitrophenol (d) Phenol or 4-cyanophenol (e) 2,5-Dinitrophenol or 2,6-dinitrophenol 24.15 Choose the reaction in each of the following pairs that proceeds at the faster rate. Explain your reasoning. (a) Basic hydrolysis of phenyl acetate or m-nitrophenyl acetate (b) Basic hydrolysis of m-nitrophenyl acetate or p-nitrophenyl acetate (c) Reaction of ethyl bromide with phenol or with the sodium salt of phenol (d) Reaction of ethylene oxide with the sodium salt of phenol or with the sodium salt of p-nitrophenol (e) Bromination of phenol or phenyl acetate 24.16 Pentafluorophenol is readily prepared by heating hexafluorobenzene with potassium hydrox- ide in tert-butyl alcohol: What is the most reasonable mechanism for this reaction? Comment on the comparative ease with which this conversion occurs. 24.17 Each of the following reactions has been reported in the chemical literature and proceeds cleanly in good yield. Identify the principal organic product in each case. (a) (b) (c) (d) heat CH 3 CNH OCH 2 CH O CH 2 HNO 3 acetic acid, heat CH OCH 3 HO O ONa H11001 ClCH 2 CHCH 2 OH OH K 2 CO 3 acetone OH OCH 3 H11001 CH 2 CHCH 2 Br F F F FF F Hexafluorobenzene F OH F FF F Pentafluorophenol (71%) 1. KOH, (CH 3 ) 3 COH, reflux, 1 h 2. H H11001 966 CHAPTER TWENTY-FOUR Phenols Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (e) (f) (g) (h) (i) (j) (k) 24.18 A synthesis of the analgesic substance phenacetin is outlined in the following equation. What is the structure of phenacetin? p-Nitrophenol phenacetin 1. CH 3 CH 2 Br, NaOH 2. Fe, HCl; then HO H11002 3. CH 3 COCCH 3 O X O X Cl OH Cl Cl H11001 C 6 H 5 N H11001 N Cl H11002 CH 3 NH 2 H11001 OH C O O heat acetic acid OH Cl Cl H11001 2Cl 2 NaOH dimethyl sulfoxide, 90°C CH 3 H 3 C OH H11001 Cl NO 2 AlCl 3 OCCH 3 CH 3 CH(CH 3 ) 2 O K 2 Cr 2 O 7 H 2 SO 4 Cl OH OH acetic acid OCH 2 CH 3 NO 2 OH H11001 Br 2 Problems 967 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.19 Identify compounds A through C in the synthetic sequence represented by equations (a) through (c). (a) (b) (c) 24.20 Treatment of 3,5-dimethylphenol with dilute nitric acid, followed by steam distillation of the reaction mixture, gave a compound A (C 8 H 9 NO 3 , mp 66°C) in 36% yield. The nonvolatile residue from the steam distillation gave a compound B (C 8 H 9 NO 3 , mp 108°C) in 25% yield on extraction with chloroform. Identify compounds A and B. 24.21 Outline a reasonable synthesis of 4-nitrophenyl phenyl ether from chlorobenzene and phenol. 24.22 As an allergen for testing purposes, synthetic 3-pentadecylcatechol is more useful than nat- ural poison ivy extracts (of which it is one component). A stable crystalline solid, it is efficiently prepared in pure form from readily available starting materials. Outline a reasonable synthesis of this compound from 2,3-dimethoxybenzaldehyde and any necessary organic or inorganic reagents. 24.23 Describe a scheme for carrying out the following synthesis. (In the synthesis reported in the literature, four separate operations were required.) 24.24 In a general reaction known as the cyclohexadienone-phenol rearrangement, cyclohexa- dienones are converted to phenols under conditions of acid catalysis. An example is Write a reasonable mechanism for this reaction. H H11001 O (100%) OH OCCH 3 CH 3 CH 3 O OH O CH 3 CH 3 O CH 2 CH OCH 3 OH CH 2 OH OH (CH 2 ) 14 CH 3 3-Pentadecylcatechol Compound B H11001 H 2 O Compound C (C 6 H 5 BrO) H H11001 heat Compound A H11001 Br 2 Compound B (C 6 H 5 BrO 7 S 2 ) 1. HO H11002 2. H H11001 Phenol H11001 H 2 SO 4 Compound A (C 6 H 6 O 7 S 2 ) heat 968 CHAPTER TWENTY-FOUR Phenols Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 24.25 Treatment of p-hydroxybenzoic acid with aqueous bromine leads to the evolution of carbon dioxide and the formation of 2,4,6-tribromophenol. Explain. 24.26 Treatment of phenol with excess aqueous bromine is actually more complicated than expected. A white precipitate forms rapidly, which on closer examination is not 2,4,6-tribro- mophenol but is instead 2,4,4,6-tetrabromocyclohexadienone. Explain the formation of this prod- uct. 24.27 Treatment of 2,4,6-tri-tert-butylphenol with bromine in cold acetic acid gives the compound C 18 H 29 BrO in quantitative yield. The infrared spectrum of this compound contains absorptions at 1630 and 1655 cm H110021 . Its 1 H NMR spectrum shows only three peaks (all singlets), at H9254 1.2, 1.3, and 6.9 ppm, in the ratio 9:18:2. What is a reasonable structure for the compound? 24.28 Compound A undergoes hydrolysis of its acetal function in dilute sulfuric acid to yield 1,2- ethanediol and compound B (C 6 H 6 O 2 ), mp 54°C. Compound B exhibits a carbonyl stretching band in the infrared at 1690 cm H110021 and has two singlets in its 1 H NMR spectrum, at H9254 2.9 and 6.7 ppm, in the ratio 2:1. On standing in water or ethanol, compound B is converted cleanly to an isomeric substance, compound C, mp 172–173°C. Compound C has no peaks attributable to carbonyl groups in its infrared spectrum. Identify compounds B and C. 24.29 One of the industrial processes for the preparation of phenol, discussed in Section 24.6, includes an acid-catalyzed rearrangement of cumene hydroperoxide as a key step. This reaction proceeds by way of an intermediate hemiacetal: You learned in Section 17.8 of the relationship among hemiacetals, ketones, and alcohols; the for- mation of phenol and acetone is simply an example of hemiacetal hydrolysis. The formation of the hemiacetal intermediate is a key step in the synthetic procedure; it is the step in which the aryl–oxygen bond is generated. Can you suggest a reasonable mechanism for this step? 24.30 Identify the following compounds on the basis of the information provided: (a) C 9 H 12 O: Its infrared and 1 H NMR spectra are shown in Figure 24.5. (b) C 9 H 11 BrO: Its infrared and 1 H NMR spectra are shown in Figure 24.6. C(CH 3 ) 2 OOH Cumene hydroperoxide H 2 SO 4 H 2 O H 2 O OC(CH 3 ) 2 OH Hemiacetal OH Phenol H11001 CH 3 CCH 3 O Acetone O O O Compound A Problems 969 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 02040 Chemical shift (δ, ppm) 80100 60120140180200 160 C C CH CH CH 2 CH 2 CH 3 (b) Wave number, cm H110021 Transmittance (%) Wavelength, H9262m (a) FIGURE 24.5 (a) Infrared and (b) 13 C NMR spectra of the compound C 9 H 12 O (Problem 24.30a). Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Wave number, cm H110021 Transmittance (%) Wavelength, H9262m (a) 020406080 Chemical shift (δ, ppm) 120140160180200 100 C CH CH CH CH 2 CH 2 CH 2 (b) FIGURE 24.6 (a) Infrared and (b) 13 C NMR spectra of the compound C 9 H 11 BrO (Problem 24.30b). Problems 971 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website