3。8 CHAPTER 24 PHENOLS henols are compounds that have a hydroxyl group bonded directly to a benzene or benzenoid ring. The parent compound of this group, C6HsOH, 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 ph nol.* This, like many other entrenched common names, is an acceptable IUPAC name Likewise. 0- and p-cresol e 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 H3 Phenol -Cresol 5-Chloro-2-methylpheno The systematic na 93 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
939 CHAPTER 24 PHENOLS Phenols are compounds that have a hydroxyl group bonded directly to a benzene or benzenoid ring. The parent compound of this group, C6H5OH, called simply phenol, is an important industrial chemical. Many of the properties of phenols are analogous 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 example, 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 phenol.* 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 derivatives 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. Substituents are cited in alphabetical order. OH Phenol OH CH3 m-Cresol OH CH3 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
CHAPTER TWENTY-FoUR Phenols 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 OH OH OH rocatechol is often called 1.2-Benzenediol 3-Benzenediol 1. 4-Benzenediol 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 (d)4-Chlororesorcinol SAMPLE SOLUTION (a) Like the dihydroxybenzenes, the isomeric trihydroxy benzenes have unique names. Pyrogallol, used as a developer of photographi film, is 1, 2, 3-benzenetriol. The three hydroxyl groups occupy adjacent positions a benzene ring (1, 2, 3-benzenetriol) 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. HO -COH CH p-Hydroxybenzoic acid 2-Hydroxy-4-methy lacet 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 108.5C-0-H angle of methanol 142pm this chapter is a molecular mo structure and electrostatic po- Methanol Back Forward Main MenuToc Study Guide ToC Student o 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 indicated in parentheses below the structures shown here. These common names are permissible IUPAC names. The common names for the two hydroxy derivatives of naphthalene are 1-naphthol 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 trihydroxybenzenes 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 determining 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° CH3 Methanol HO COH O p-Hydroxybenzoic acid CH3 CCH3 O OH 5 6 4 1 3 2 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 potential. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
24.3 Physical Properties As weve seen on a number of occasions, bonds to sp-hybridized carbon are shorter than those to sp-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 +Oh +OH H Most stable lewis Dipolar resonance forms of phenol tructure for 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 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 cal properties of with water(Figure 241b). Thus, phenols have higher melting points and boiling points and are more soluble in water than arenes and aryl halides of comparable molecular ected in Appendix 1 weight. Table 24.1 compares phenol, toluene, and fluorobenzene with regard to these 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. TABLE 24.1 Comparison of Physical Properties of an Arene, a Phenol, and an Aryl Halide Toluene, Phenol Fluorobenzene Physical property C6H5CH3 C6HsOH Molecular weight Melting point 95°c 43°C -41°C Boiling point (1 atm) 111°C 32°C Solubility in water(25.C) 0.05g/100mL 8.2g/100mL 0.2g/100ml Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
As we’ve seen on a number of occasions, bonds to sp2 -hybridized carbon are shorter than those to sp3 -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 attributed 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 intramolecular 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 H H H H H OH Most stable Lewis structure for phenol H H H H H OH H H H H H OH H H H H H OH 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, C6H5CH3 92 95°C 111°C 0.05 g/100 mL Phenol, C6H5OH 94 43°C 132°C 8.2 g/100 mL Fluorobenzene, C6H5F 96 41°C 85°C 0.2 g/100 mL Compound Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-FoUR Phenols FIGURE 24.1(a)A hy drogen bond between two phenol molecules; (b) hydr gen bonds between water and phenol molecules Intramolecular hydrogen bond H 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 wintergr Methyl salicylate boils over 50oC 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 Ka of approximately 10(pKa 5), whereas the Kas of alcohols are in the 10-16 to 10-20 range(pka 16-20). The Ka for most phenols is about 10-0(pka 10 Back Forward Main MenuToc Study Guide ToC Student o 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 ionization constants Ka of approximately 105 (pKa 5), whereas the Ka’s of alcohols are in the 1016 to 1020 range (pKa 16–20). The Ka for most phenols is about 1010 (pKa 10). N O O H O Intramolecular hydrogen bond in o-nitrophenol 942 CHAPTER TWENTY-FOUR Phenols (a) (b) -------------------- --------------- --------------- FIGURE 24.1 (a) A hydrogen bond between two phenol molecules; (b) hydrogen bonds between water and phenol molecules. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
24.4 Acidity of Phenols To help us understand why phenols are more acidic than alcohols, let's compare Because of its acidity, phenol the ionization equilibria for phenol and ethanol. In particular, consider the differences in was known as carbolic acid charge delocalization in ethoxide ion and in phenoxide ion. The negative charge in ethox- when Joseph Lister intro. ide ion is localized on oxygen and is stabilized only by solvation forces CH3CH20-H H+ CH3CH20: Ka=10 (pKa=16) were then a life-threatening hazard in even minor surge- Ethanol Proton Ethoxide ion he negative charge in phenoxide ion is stabilized both by solvatic elec tron delocalization into the ring. Ka=10-10(pKa=10) Proton Phenoxide ion Electron delocalization in phenoxide is represented by resonance among the nto the ring H H 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 salt, which is extracted into the aqueous phase How do we know that water OH+ H,O tive pk. values? Phenol Hydroxide ion Phenoxide ion Water (stronger acid (weaker base) weaker acid) On shaking an ether solution of a phenol and a carboxylic acid with dilute sodium bonate, the carboxylic acid is converted quantitatively to its sodium salt and extr into the aqueous phase. The phenol remains in the ether phase OH+ HCO3 O+ H,CO3 ger acid than phenol? What are their Bicarbonate ion noxide ion Carbonic acid espective pKa values? Back Forward Main MenuToc Study Guide ToC Student o 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 ethoxide 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 electron 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 solution 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 bicarbonate, the carboxylic acid is converted quantitatively to its sodium salt and extracted into the aqueous phase. The phenol remains in the ether phase. K 1 OH Phenol (weaker acid) HCO3 Bicarbonate ion (weaker base) O Phenoxide ion (stronger base) H2CO3 Carbonic acid (stronger acid) K 1 OH Phenol (stronger acid) HO Hydroxide ion (stronger base) O Phenoxide ion (weaker base) H2O Water (weaker acid) H H H H H O H H H H H O H H H H H O H H H H H O Ka 1010 (pKa 10) Proton H Phenol O H Phenoxide ion O Ka 1016 CH H (pKa 16) 3CH2O Ethanol Proton H CH3CH2O Ethoxide ion 24.4 Acidity of Phenols 943 Because of its acidity, phenol was known as carbolic acid when Joseph Lister introduced it as an antiseptic in 1865 to prevent postoperative bacterial infections that were then a life-threatening hazard in even minor surgical procedures. The electrostatic potential 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 phenol? What are their respective pKa values? How do we know that carbonic acid is a stronger acid than phenol? What are their respective pKa values? Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
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
