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862 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

is converted into its conjugate-base phenoxide ion, which, because it is ionic, is the species that actually dissolves in the aqueous solution. Solubility in 5% NaOH solution is a qualitative test for phenols (and other compounds of equal or greater acidity). Phenoxides, like alkoxides, can be used as nucleophiles. For example, aryl ethers can be prepared by the reaction of a phenoxide anion and an alkyl halide.

O _ Br CH2CH2CH3 O CH2CH2CH3 Br _ (18.68) cL 2 3 3 2 L cLL2 + 332 2 21-bromopropane 2 2 phenoxide propoxybenzene ion (63% yield)

This is another example of the Williamson ether synthesis (Sec. 11.1A). Note that the reaction of sodium propoxide, the sodium salt of 1-propanol, with bromobenzene, would not be a sat- isfactory synthesis of this ether. (Why? See Sec. 18.1.)

PROBLEMS 18.31 Outline a preparation of each of the following compounds from the indicated starting mate- rial and any other reagents. (a) p-nitroanisole from p-nitrophenol (b) 2-phenoxyethanol from phenol 18.32 The following compound, unlike most phenols, is soluble in neutral aqueous solution, but insoluble in aqueous base. Explain this unusual behavior.

HO N(CH| 3)3 Cl- 2 LcL 2

18.8 OXIDATION OF PHENOLS TO QUINONES

Even though phenols do not have hydrogen at their a-carbon atoms, they do undergo oxida- tion. The most common oxidation products of phenols are quinones.

OH O " Na Cr O 2 2 7 (18.69) H SO i 2 4 e

"OH O hydroquinone p-benzoquinone (86–92% yield)

OH O H C CH H C CH 3 " 3 3 3 Na Cr O % M 2 2 7 % M (18.70) H2SO4 r H2O e H3C M H3C M 2,3,6-trimethylphenol O 2,3,5-trimethyl-1,4-benzoquinone (50% yield) 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 863

18.8 OXIDATION OF PHENOLS TO QUINONES 863

OH O

) dry ether H C (18.71) H3C OH Ag O 3 O LvL 2 L/

4-methylcatechol 4-methyl-1,2-benzoquinone (unstable red crystals) (68% yield)

As Eqs. 18.69–18.71 illustrate, p-hydroxyphenols (hydroquinones), o-hydroxyphenols (cate- chols), and phenols with an unsubstituted position para to the hydroxy group are oxidized to quinones. A quinone is any compound containing either of the following structural units.

O O O

e

O an ortho-quinone a para-quinone

If the quinone oxygens have a 1,4 (para) relationship, the quinone is called a para-quinone; if the oxygens are in a 1,2 (ortho) arrangement, the quinone is called an ortho-quinone. The fol- lowing compounds are typical quinones.

O O O S O derived from e S O o-benzoquinone O naphthalene (1,2-benzoquinone) p-benzoquinone 1,4-naphthoquinone (1,4-benzoquinone)

O 8 9 1 7 2 derived from 6 3 5 10 4 O anthracene 9,10-anthraquinone

As illustrated by the preceding structures, the names of quinones are derived from the names of the corresponding aromatic hydrocarbons: benzoquinone is derived from benzene, naph- thoquinone from naphthalene, and so on. Ortho-quinones, particularly ortho-benzoquinones, are typically considerably less stable than their para-quinone isomers. One reason for this difference is that in ortho-quinones, the ends of the CAO bond dipoles with like charges are close together and therefore have a 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 864

864 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

repulsive, destabilizing interaction. In para-quinones these dipoles are pointed in opposite di- rections and are farther apart. O O O

O o-benzoquinone p-benzoquinone like charges in the bond dipoles bond dipoles have opposite directions are close together and are farther apart

A number of quinones occur in nature. Coenzyme Q, shown in the following structures in its oxidized form ubiquinone, is an important factor in the respiratory chain localized in the mitochondrion that converts oxygen ultimately into water and harnesses the energy thus re- leased to synthesize adenosine triphosphate (ATP), an important “biochemical fuel.” Doxoru- bicin (adriamycin), isolated from a microorganism, is an important antitumor drug. O O O OH

CCH2OH

CH3O CH3 M " CH % M 3 OH e CH O CH CH A"C CH H 3 M 2 2 L 10 O CH3"O O "OH O sugar L coenzyme Q doxorubicin (ubiquinone) (adriamycin)

The oxidation of phenols by air (O2) to colored, quinone-containing products is the reac- tion responsible for the darkening that is observed when some phenols are stored for a long time. The oxidation of hydroquinone and its derivatives to the corresponding p-benzoquinones can also be carried out reversibly in an electrochemical cell. Oxidation potentials of a number of phenols with respect to standard electrodes are well known.

PROBLEM 18.33 Postulate a structure for the compound formed when ubiquinone undergoes a two-electron reduction.

Practical Applications of Phenol Oxidation The oxidation of phenols has several im- portant practical applications. For example, phenols are sometimes used to inhibit free-radical reactions that result in the oxidation of other compounds (Sec. 5.6C). The basis of this effect is that many free radicals (R· in Eq. 18.72a) abstract a hydrogen from hydroquinone to form a very stable radical called a semiquinone. R R H 8 L

O H O

1 12 L 1 12 8 M M (18.72a) i r OM OM 3 3 "H "H a semiquinone 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 865

18.8 OXIDATION OF PHENOLS TO QUINONES 865

(The semiquinone radical, like the benzyl radical (Eq. 17.10, p. 793), is resonance-stabilized, as shown in Eq. 18.72b.) A second free radical can react with the semiquinone to complete its ox- idation to quinone.

O O O 2 3 2 3 2 2 3 M 8 R H (18.72b) i O O + L OM M 8 3 2 3 2 3 "H "H R 8 Hydroquinone thus terminates free-radical chain reactions by intercepting free-radical intermediates R and reducing them to RH. The effectiveness8 of several widely used food preservatives is based on reactions such as these. Examples of such preservatives are “butylated hydroxytoluene” (BHT) and “butylated hydroxyanisole” (BHA).

OH OH OH (CH ) C C(CH ) C(CH ) 3 3 " 3 3 " 3 3 " % M M i i + i %C(CH3)3 "CH3 "OCH3 "OCH3 BHT BHA

Oxidation involving free-radical processes is one way that foods discolor and spoil. A preser- vative such as BHT inhibits these processes by donating its OH hydrogen atom to free radicals in the food (as in Eq. 18.72a). The BHT is thus transformed into a phenoxy radical, which is too stable and unreactive to propagate radical chain reactions. Although the use of BHT and BHA as food additives has generated some controversy because of their potential side effects, without such additives foods could not be stored for any appreciable length of time or trans- ported over long distances. Vitamin E, a phenol, is the major compound in the blood responsible for preventing oxida- tive damage by free radicals. Vitamin E acts by terminating radical chains in the manner shown in Eq. 18.72a.

CH3 HO " % CH3 i` H3C O M CH3 H CH3 H CH3 CH3 "CH3 a-tocopherol a major form of vitamin E 18_BRCLoudon_pgs4-3.qxd 11/26/08 9:09 AM Page 866

866 CHAPTER 18 • THE CHEMISTRY OF ARYL HALIDES, VINYLIC HALIDES, AND PHENOLS. TRANSITION-METAL CATALYSIS

Poison Ivy and Itchy Quinones Over half of the people in the United States suffer from allergy to poison ivy,poison oak,and poison sumac. The active principle in these plants is a family of catechol derivatives known collectively as urushiol. OH OH

urushiol (one of several components)

(The various urushiol components differ in the number,positions,and possibly the stereochemistry of the side-chain double bonds.) The allergic reaction is not caused by the catechol itself, but rather by its oxidation product, an o-quinone:

OH O OH [O] O enzyme HH (18.73) biological oxidation C C R R

(CH2)7 (CH2)5CH3

The long hydrocarbon side chain of urushiol probably imbeds itself into the lipid bilayer (Sec. 8.5A) of a skin-cell membrane, thus immobilizing it near membrane-localized oxidizing enzymes. Ortho- quinones are examples of a, b-unsaturated ketones, which are compounds in which a ketone car- bonyl group (CAO) is conjugated with a carbon–carbon double bond. As we’ll explore in Sec. 22.8, these compounds undergo rapid conjugate addition with nucleophiles, including nucleophiles available in the cell, such as the thiol and amino groups of proteins. Using the thiol group of a pro- tein as an example, a typical addition reaction occurs as follows: O OH O O P SH + (18.74a) conjugate P S protein R addition R H

A subsequent rapid reaction with Brønsted acids and bases forms a substituted catechol.

OH OH

..

.. ..

.. O O.. H B

P S R P S R H

.. OH B .. OH.. + B .. P S R (18.74b)

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18.9 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF PHENOLS 867

Ortho-quinones are not aromatic, but the catechol addition products are; the aromatic stabilization of the product makes the reaction irreversible.These reactions result in an irreversibly modified pro- tein,which is now sensed as “foreign”by the immune system.The resulting biological response is the all-too-familiar allergic reaction—the skin eruptions and the intense itch.

PROBLEMS 18.34 Given the structure of phenanthrene, draw structures of (a) 9,10-phenanthraquinone (b) 1,4-phenanthraquinone

10 1 9 2

3 8 4 7 5 6

phenanthrene Indicate whether each is an o- or a p-quinone. 18.35 Complete the following reactions. (a) OH (b) OH NO 2 ) Cr(VI) " Cr(VI) M HO OH H SO H SO 2 4 i 2 4 LvL 18.36 Draw the important resonance structures of the radicals formed when each of the following reacts with R , a general free radical. (a) vitamin E8 (b) BHT

18.37 (a) Give the structure of the product formed in the reaction of urushiol with K2CO3 and a large excess of methyl iodide. (b) Would this compound be likely to provoke the same allergic skin response as urushiol? Explain.

ELECTROPHILIC AROMATIC SUBSTITUTION 18.9 REACTIONS OF PHENOLS

Phenols are aromatic compounds, and they undergo electrophilic aromatic substitution reactions such as those described in Sec. 16.4. In some of these reactions, the OH group has special effects that are not common to other substituent groups. L Because the OH group is a strongly activating substituent, phenol can be halogenated

once under mildL conditions that are totally ineffective for benzene itself.

c c

H OH Br2 Br OH HBr (18.75) LL+ CCl4 or CS2 LL+ phenol p-bromophenol (82% yield)

Notice the mild conditions of this reaction. A Lewis acid such as FeBr3 is not required. (A so- lution of Br2 in CCl4 is the reagent usually used for adding bromine to alkenes.) But when phe-