CHAPTER TWENTY-FoUR Phenols 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 do we know that hy HO oH+ H. respective pk, values? Phenoxide ion onium ion Phenol (weaker acid)(weaker base) Many synthetic reactions involving phenols as nucleophiles are carried out in the ence of sodium or potassium hydroxide. Under these conditions the phenol is con rted d 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 TOn. Alkyl substitution produces negligible changes in acidities, as do weakly elec- ative groups attached to the ring TABLE 24.2 Acidities of Some Phenols lonization Compound constant k monosubstituted phenols 1.0×10 4.7×10-11 Recall from Section 24.1 o-Cresol hat cresols are methyl m-Cresol 80×10-11 10.1 ubstituted derivatives of phenol. o-Chlorophenol 2.7×10-9 p-Chlorophenol 7.6×10-9 chlorom 3.9×10 10×10-10 10.0 p-Methoxyphenol 6.3×10 10.2 5.9×10 7.2 6.9 2, 4-Dinitrophenol 1.1×10-4 4.0 3, 5-Dinitrophenol 20×10-7 4.2×10 Naphthols 1-Naphthol 5.9×10-1 3.5×10 9.5 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
It is necessary to keep the acidity of phenols in mind when we discuss preparation 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 converted 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 electronegative groups attached to the ring. K 1 OH Phenol (weaker acid) H3O Hydronium ion (stronger acid) O Phenoxide ion (stronger base) H2O Water (weaker base) 944 CHAPTER TWENTY-FOUR Phenols How do we know that hydronium ion is a stronger acid than phenol? What are their respective pKa values? Recall from Section 24.1 that cresols are methylsubstituted derivatives of phenol. TABLE 24.2 Acidities of Some Phenols Ionization constant Ka 1.0 1010 4.7 1011 8.0 1011 5.2 1011 2.7 109 7.6 109 3.9 109 1.0 1010 2.2 1010 6.3 1011 5.9 108 4.4 109 6.9 108 1.1 104 2.0 107 4.2 101 5.9 1010 3.5 1010 pKa 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
24.5 Substituent Effects on the acidity of phenols 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 N。oA 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 (a) Phenol or p-hydroxybenzaldehyde (b)m-Cyanophenol or p-cyanophenol 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 Ka of 2. 4 x 10, is a stronger acid than phenol Multiple substitution by strongly electron-withdrawing groups greatly increases the acidity of phenols, as the Ka values for 2, 4-dinitrophenol (Ka 1.1 X 10 )and 2,4,6- trinitrophenol(Ka 4.2 x 10)in Table 24.2 attest Back Forward Main MenuToc Study Guide ToC Student o 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 stabilizes 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 different 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 acidstrengthening, especially when ortho or para to the hydroxyl group. p-Hydroxybenzaldehyde, with a Ka of 2.4 108 , is a stronger acid than phenol. Multiple substitution by strongly electron-withdrawing groups greatly increases the acidity of phenols, as the Ka values for 2,4-dinitrophenol (Ka 1.1 104 ) and 2,4,6- trinitrophenol (Ka 4.2 101 ) in Table 24.2 attest. O CH O O CH O O N O O O N O O N O O O N O O O 24.5 Substituent Effects on the Acidity of Phenols 945 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-FoUR Phenols 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 Ib 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- cs. Almost all the phenol processes in current use. These are summarized in Table 24.3 The reaction of benzenesulfonic acid with sodium hydroxide(first entry in Table 4.3)proceeds by the addition-elimination mechanism of nucleophilic aromatic substi tution(Section 23.6). Hydroxide replaces sulfite ion(SO3)at the carbon atom that Can you recall how to pre SO,H p-Toluenesulfonic acid p-Cresol(63-72%) 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,C-labeling studies have shown that the base-promoted hydrol Can you recall how to pre 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 Can you recall how to pre sulfuric acid)and the fact that it yields two high-volume industrial chemicals: phenol pare isopropylbenzene? 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 L NaNO, H,sO HN- HO m-Nitroaniline 81-86%) 24.7 NATURALLY OCCURRING PHENOLS Phenolic com ds are commonplace natural products 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 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
24.6 SOURCES OF PHENOLS Phenol was first isolated in the early nineteenth century from coal tar, and a small portion 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 plastics. 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 substitution (Section 23.6). Hydroxide replaces sulfite ion (SO3 2) 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-toluenesulfonic acid to p-cresol under the conditions shown in the preceding equation. On the other hand, 14C-labeling studies have shown that the base-promoted hydrolysis 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 economically 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. NaNO2, H2SO4 H2O 2. H2O, heat NO2 H2N m-Nitroaniline HO NO2 m-Nitrophenol (81–86%) SO3H CH3 p-Toluenesulfonic acid OH CH3 p-Cresol (63–72%) 1. KOH–NaOH mixture, 330°C 2. H 946 CHAPTER TWENTY-FOUR Phenols Can you recall how to prepare p-toluenesulfonic acid? Can you recall how to prepare chlorobenzene? Can you recall how to prepare isopropylbenzene? Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
24.7 Naturally Occurring Phenols TABLE 24.3 Industrial Syntheses of Phenol Reaction and comments Chemical equation Reaction of benzenesulfonic acid w SO,H OH hydroxide This is the oldest method 300-350 ration of phenol. Benzene is sulfone benzenesulfonic acid heated with hydroxide Acidification of the reaction mixture Benzenesulfonic acid Phenol 1. NaOH Hydrolysis of chlorobenzene Heating chloroben- OH zene with aqueous sodium hydroxide at high pres- sure gives phenol after acidification Chlorobenzene Phenol From cumene Almost all the phenol produced in OOH the United States is prepared by this method. Oxi- dation of cumene takes place at the benzylic posi- CH(CH3)2 C(CH3) tion to give a hydroperoxide On treatment with dilute sulfuric acid, this hydroperoxide is converted Isopropylbenzene 1-Methyl-1-phenylethyl to phenol and acetone hydroperoxide OH +(CH3)2C=O hyd CH(CH3)h (isolated from defensive secretion OH HC HO CH(CH3h2 CH H2)CH (active component of marijuana) CH(CH3h2 the United States RE 24.2 Some occurr Back Forward Main MenuToc Study Guide ToC Student o 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 preparation 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 chlorobenzene with aqueous sodium hydroxide at high pressure gives phenol after acidification. From cumene Almost all the phenol produced in the United States is prepared by this method. Oxidation of cumene takes place at the benzylic position 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 SO3H Benzenesulfonic acid OH Phenol 1. NaOH, H2O 370°C 2. H OH Phenol Cl Chlorobenzene O2 CH(CH3)2 Isopropylbenzene (cumene) C(CH3)2 OOH 1-Methyl-1-phenylethyl hydroperoxide Acetone OH (CH3)2C O Phenol C(CH3)2 OOH 1-Methyl-1-phenylethyl hydroperoxide H2O H2SO4 CH(CH3)2 (CH2)4CH3 CH(CH3)2 CH(CH3)2 CH3 CH3 CH3 CH3 OH Thymol (major constituent of oil of thyme) Cl Cl OH 2,5-Dichlorophenol (isolated from defensive secretion of a species of grasshopper) O 9 -Tetrahydrocannabinol (active component of marijuana) HC OH OH OH O HC O HO HO HO HO CH3 CH3 Gossypol (About 109 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
CHAPTER TWENTY-FoUR Phenols of arene oxide intermediates formed by the enzyme-catalyzed reaction between an aro- matic ring and molecular oxygen R+0=R一mR Arene Arene oxide Phenol 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 s 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 2, 4, 6-Tribromo-3- Hydrogen Other typical electrophilic aromatic substitution reactions---nitration(second entry), sul fomation(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-lsopropyl-5-methylphenol (thymol)treated with sodium nitrite and dilute hydrochloric acid d)p-Cresol treated with propanoyl chloride and aluminum chloride Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
of arene oxide intermediates formed by the enzyme-catalyzed reaction between an aromatic 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 electrophilic 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 aromatic substitution in phenols occurs far faster, and under milder conditions, than in benzene. 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 reaction 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 following example, all three positions that are ortho or para to the hydroxyl undergo rapid substitution: Other typical electrophilic aromatic substitution reactions—nitration (second entry), sulfonation (fourth entry), and Friedel–Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo electrophilic substitution reactions that are limited to only the most active aromatic compounds; these include nitrosation (third entry) and coupling with diazonium salts (seventh entry). PROBLEM 24.6 Each of the following reactions has been reported in the chemical literature and gives a single organic product in high yield. Identify the product 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 H2O 25°C OH F m-Fluorophenol 3Br2 Bromine Br OH F Br Br 2,4,6-Tribromo-3- fluorophenol (95%) 3HBr Hydrogen bromide enzyme R Arene O2 R O Arene oxide HO R Phenol 948 CHAPTER TWENTY-FOUR Phenols Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website