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Home , Acylation, Acyl group, Alkene, Alkylation, Benzenesulfonic acid, Carbocation

16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 750

750 CHAPTER 16 • THE OF AND ITS DERIVATIVES

This hybridization allows one of its pairs to occupy a 2p orbital, which has the same size, shape, and orientation as the 2p orbitals of the ring. In other words, an 2p orbital overlaps more effectively with the carbon 2p orbitals of the ring than an oxygen sp3 or- bital would. (We learned about the same effect in -stabilized allylic systems; p. 713). The UV spectrum of anisole is a direct consequence of this overlap.

PROBLEMS 16.10 (a) Explain why compound A has a UV spectrum with considerably greater lmax values and intensities than are observed for .

C2H5 C2H5 lmax 256 nm (e 20,000) LLL = 283 nm (e = 5,100) = A (b) In view of your answer to part (a), explain why the UV spectra of compounds B and C are virtually identical.

CH3 H3C CH3

$ $ "

$ H3C $ CH3 Lv vL i H C 3 M%CH3 H C CH 3 3 C B bimesityl lmax 266 nm (e 200) = = lmax 266 nm (e 700) = =

16.11 How could you distinguish (Ph CHACH2) from ethylbenzene by UV spec- troscopy? L

ELECTROPHILIC AROMATIC SUBSTITUTION 16.4 REACTIONS OF BENZENE

The most characteristic reaction of benzene and many of its derivatives is electrophilic aro- matic substitution. In an electrophilic aromatic , a of an aro- matic ring is substituted by an —that is, by a Lewis . The general pattern of an electrophilic aromatic substitution reaction is as follows, where E is the electrophile:

H EY E H Y (16.1) LL+ L + L

(Note that in this reaction and in others that follow, only one of the six benzene is shown explicitly to emphasize that one hydrogen is lost in the reaction.) All electrophilic aromatic substitution reactions occur by similar mechanisms. This section surveys some of the most common electrophilic aromatic substitution reactions and their mechanisms. 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 751

16.4 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE 751

A. of Benzene When benzene reacts with under harsh conditions—liquid bromine, no , and

the Lewis acid FeBr3 as a catalyst—a reaction occurs in which one bromine is substituted for a ring hydrogen.

FeBr or Fe 3 (16.2) H Br2 (0.2 equiv.) Br HBr L + L + benzene bromobenzene (50% yield)

(Because reacts with Br2 to give FeBr3, iron filings can be used in place of FeBr3.) An analogous chlorination reaction using Cl2 and FeCl3 gives chlorobenzene. This reaction of benzene with differs from the reaction of with halogens in two important ways. First is the type of product obtained. Alkenes react spontaneously with bromine and , even in dilute solution, to give addition products. Br

Br2 (16.3) y ` + Br Halogenation of benzene, however, is a substitution reaction; a ring hydrogen is replaced by a . Second, the reaction conditions for benzene halogenation are much more severe than the conditions for addition of halogens to an . The first step in the mechanism of benzene bromination is the formation of a complex

between Br2 and the Lewis acid FeBr3. 1 1 1 1

| Br Br FeBr3 Br Br FeBr_ 3 (16.4) 3 1 L 1 3 3 1 LL1 Formation of this complex results in a formal positive charge on one of the bromines. A posi- tively charged bromine is a better electron acceptor, and thus a better , than a

bromine in Br2 itself. Another (and equivalent) explanation of the leaving-group effect is that _FeBr4 is a weaker than Br_. (Remember from Sec. 9.4F that weaker bases are better leaving groups.) _FeBr4 is essentially the product of a Lewis acid–base association reaction of Br_ with FeBr3. Therefore, in _FeBr4, an electron pair on Br_ has already been donated to Fe, and is thus less available to act as a base, than a “naked” electron pair on Br_ itself.

a better electron acceptor a weaker electron acceptor

and better leaving group and poorer leaving group

1 1 1 1

| Nuc Br Br FeBr_ 3 Nuc Br Br

(a )3 3 1 L 1 L 3 3 1 L 1 3

1 1 1 1

(16.5) Nuc| Br Br FeBr_ 3 Nuc| Br Br _ L 1 3 + 3 1 L L 1 3 + 3 1 3 a weaker base a stronger base 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 752

752 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES

As you learned in Sec. 9.4F, Br is a good leaving group. The fact that a much better leaving group than Br is required Lfor electrophilic aromatic substitution illustrates how unreactive the benzeneL ring is. In the second step of the mechanism, this complex reacts with the p of the ben-

zene ring. The p electrons act as a nucleophile, the Br as an electrophile, and _FeBr4 as a leav- ing group.

electrophile nucleophile | Br Br FeBr_ 3 3 12 L 12 L H /L leaving group

| Br Br Br 12 3 12 3 12 3 FeBr_ 4 (16.6) M | M M ΄ /n%H x%H %H ΄ + | Although this step results in the formation of a resonance-stabilized , it also disrupts the aromatic stabilization of the benzene ring. Harsh conditions (high reagent concentrations, high temperature, and a strong Lewis acid catalyst) are required for this reaction to proceed at a useful rate because this step does not occur under the much milder conditions used to bring about bromine addition to an alkene.

The reaction is completed when a (complexed to FeBr3) acts as a base to remove the ring proton, regenerate the catalyst FeBr3, and give the products bromobenzene and HBr.

| Br Br HBr FeBr (16.7) M 12 3 3 /%H Br FeBr_ 3 vL 12 3 ++12 3 3 12 L Recall that loss of a b-proton is one of the characteristic reactions of (Sec. 9.6B). Another typical reaction of carbocations—reaction of bromide ion at the electron-deficient car- bon itself—doesn’t occur because the resulting addition product would not be aromatic:

Br FeBr_ 3 H 3 12 L H Br ) Br " 12Br3 | M FeBr3 (16.8) /MH /MH + % does not occur % (not aromatic) By losing a b-proton instead (Eq. 16.7), the carbocation can form bromobenzene, a stable aro- matic compound.

PROBLEM 16.12 A small amount of a by-product, p-dibromobenzene, is also formed in the bromination of benzene shown in Eq. 16.2. Write a curved-arrow mechanism for formation of this compound. 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 753

16.4 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE 753

B. Electrophilic Aromatic Substitution Halogenation of benzene is one of many electrophilic aromatic substitution reactions. The bromination of benzene, for example, is an aromatic substitution because a hydrogen of ben- zene (the that undergoes substitution) is replaced by another group (bromine). The reaction is electrophilic because the substituting group reacts as an elec- trophile, or Lewis acid, with the benzene p electrons. In bromination, the Lewis acid is a

bromine in the complex of bromine and the FeBr3 catalyst (Eq. 16.6). We’ve considered two other types of substitution reactions: nucleophilic substitution (the

SN2 and SN1 reactions, Secs. 9.4 and 9.6) and free- substitution (halogenation of alka- nes, Sec. 8.9A). In a nucleophilic substitution reaction, the substituting group acts as a nucle- ophile, or Lewis base; and in free-radical substitution, free-radical intermediates are involved. Electrophilic aromatic substitution is the most typical reaction of benzene and its deriva- tives. As you learn about other electrophilic substitution reactions, it will help you to under- stand them if you can identify in each reaction the following three mechanistic steps:

Step 1 Generation of an electrophile. The electrophile in bromination is the complex of bromine

with FeBr3, formed as shown in Eq. 16.4. Step 2 Nucleophilic reaction of the p electrons of the aromatic ring with the electrophile to form a resonance-stabilized carbocation intermediate.

a tetrahedral, sp3-hybridized carbon; no longer involved in the p-electron system nucleophile H H + .. X (16.9a) E E X resonance-stabilized electrophile carbocation intermediate leaving group

The electrophile approaches the p-electron cloud of the ring above or below the plane of the . In the carbocation intermediate, the carbon at which the electrophile reacts becomes sp3-hybridized and tetrahedral. This step in the bromination mechanism is Eq. 16.6.

Step 3 Loss of a proton from the carbocation intermediate to form the substituted aromatic com- pound. The proton is lost from the carbon at which substitution occurs. This carbon again be- comes part of the aromatic p-electron system.

.. X H E + H X (16.9b) E

This step in the bromination mechanism is Eq. 16.7. This sequence is classified as electrophilic substitution because we focus on the nature of the group—an electrophile—that reacts with the aromatic ring. However, the mechanism re- ally involves nothing fundamentally new: like both (Sec. 5.1) and nucle- ophilic substitution (Sec. 9.1), the reaction involves the reactions of , elec- trophiles, and leaving groups. 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 754

754 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES

Study Problem 16.1 Give a curved-arrow mechanism for the following electrophilic substitution reaction.

D SO H 2 4 D L L

Solution Construct the mechanism in terms of the three preceding steps. Step 1 In this reaction, a hydrogen of the benzene ring has been replaced by an isotope D, which must

come from the D2SO4. Because protons (in the form of Brønsted ) are good , the

D2SO4 itself can serve as the electrophile. Step 2 Reaction of the benzene p electrons with the electrophile involves of the benzene ring by the isotopically substituted acid: H D OSO3D L 21 ) %D _OSO3D i a 3 21 | resonance-stabilized carbocation intermediate (If you’re asking where that “extra” hydrogen in the carbocation came from, don’t forget that each carbon of the benzene ring has a single hydrogen that is not shown explicitly in the skeletal struc- ture. One of these is shown in the carbocation because it is involved in the next step.) You should draw the resonance structures of the carbocation intermediate.

Step 3 Removal of the proton gives the final product:

H _OSO3D D ) 3 21 M H OSO D %D 3 a i + L 21 |

C. of Benzene Benzene reacts with concentrated , usually in the presence of a catalyst,

to form . In this reaction, called nitration, the nitro group, NO2, is introduced into the benzene ring by electrophilic substitution. L

H2SO4 H HONO2 NO2 H2O (16.10) L + L + nitric benzeneacid nitrobenzene (81% yield)

This reaction fits the mechanistic pattern of the electrophilic aromatic substitution reaction outlined in the previous section:

Step 1 Generation of the electrophile. In nitration, the electrophile is |NO2, the . This ion is formed by the acid-catalyzed removal of the elements of from HNO3. 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 755

16.4 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE 755

O O _ 5 _ 21 3 21 3 HO3SO H HO |N) HO3SO _ H O| |N) (16.11a) 21 LL12 12 3 L L @O "H @O 3 3 3 3

O 5 _ 21 3 H O| |N) H2O O AA|N O (16.11b) L L 21 + 21 21 "H @O nitronium ion 3 3 Step 2 Reaction of the benzene p electrons with the electrophile to form a carbocation inter- mediate. O 3S3 O_ |N 3 2 3 S | "N| H O O (16.11c) M # vL 3 3 /%H 1 3 (Notice that either of the can accept the electron pair.)

Step 3 Loss of a proton from the carbocation to give a new aromatic compound.

O

_

1 3 2 3 1 O _ | "N| 21 3 O N|) H O SO3H (16.11d) M # /%H 1 vL+ L1 L @O O SO H _ 3 3 3 12 L (from3 Eq. 16.11a)

Nitration is the usual way that nitro groups are introduced into aromatic rings.

D. Sulfonation of Benzene Another electrophilic substitution reaction of benzene is its conversion into benzenesulfonic acid.

H2SO4 H SO3 SO3H (16.12) L + L benzenetrioxide benzenesulfonic acid (52% yield)

(Sulfonic acids were introduced in Sec. 10.3A as their derivatives.) This reaction, called sulfonation, occurs by two mechanisms that operate simultaneously. Both mechanisms involve , a fuming liquid that reacts violently with water to give

H2SO4. The source of SO3 for sulfonation is usually a solution of SO3 in concentrated H2SO4 called fuming sulfuric acid or oleum. This material is one of the most acidic Brønsted acids available commercially. 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 756

756 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES

In one sulfonation mechanism, the electrophile is neutral sulfur trioxide. When sulfur trioxide reacts with the benzene ring p electrons, an oxygen accepts the electron pair dis- placed from sulfur.

OO O O_ 2 21 3 ( S( 1 O S @S)A O S H O | S O H OSO H ) _ 3 vL /$H vLS L12 3 L 12 O

_ OSO3H 3 12 (from solvent) O S S OH OSO H (16.13) _ 3 vLS L 12 + 3 12 O Sulfonic acids such as benzenesulfonic acid are rather strong acids. (Notice the last equi- librium in Eq. 16.13 and the structural resemblance of benzenesulfonic acid to another strong acid, sulfuric acid.) Sulfonation, unlike many electrophilic aromatic substitution reactions, is reversible. The

SO3H () group is replaced by a hydrogen when sulfonic acids are heated with Lsteam (Problem 16.50, p. 782).

PROBLEMS 16.13 A second sulfonation mechanism involves protonated sulfur trioxide as the electrophile.

Show the protonation of SO3, and draw a curved-arrow mechanism for the reaction of pro- tonated SO3 with benzene to give benzenesulfonic acid. 16.14 A compound called p-toluenesulfonic acid is formed when is sulfonated at the para position. Draw the structure of this compound, and give the curved-arrow mechanism for its formation.

E. Friedel–Crafts of Benzene The reaction of an halide with benzene in the presence of a Lewis acid catalyst gives an alkylbenzene.

AlCl 3 (16.14) H Cl CH CH2CH3 (0.1 equiv.) CH CH2CH3 HCl L + LL L L + "CH3 "CH3 benzene (large excess) sec-butyl sec-butylbenzene (71% yield) This reaction is an example of a Friedel–Crafts alkylation. Recall that an alkylation is a reaction that results in the transfer of an alkyl group (Sec. 10.3B). In a Friedel–Crafts alky- lation, an alkyl group is transferred to an aromatic ring in the presence of an acid catalyst. In the preceding example, the alkyl group comes from an alkyl halide and the catalyst is the

Lewis acid aluminum trichloride, AlCl3. The electrophile in a Friedel–Crafts alkylation is formed by the complexation of the Lewis

acid AlCl3 with the halogen of an alkyl halide in much the same way that the electrophile in 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 757

16.4 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE 757

the bromination of benzene is formed by the complexation of FeBr3 with Br2 (Eq. 16.4, p. 751). If the alkyl halide is secondary or tertiary, this complex can further react to form car-

bocation intermediates.

1 1

| _ _ R Cl AlCl3 R Cl AlCl3 R| AlCl4 (16.15a) L 1 3 LL1 carbocation

Either the alkyl halide–Lewis acid complex, or the carbocation derived from it, can serve as the

electrophile in a Friedel–Crafts alkylation. 1

| R Cl AlCl_ 3 LL1 H L alkylation by the complex R | or AlCl_ (16.15b) ) 4 $H _ R| AlCl4 H L alkylation by the carbocation

Compare the role of AlCl3 in enhancing the effectiveness of the chloride leaving group with the similar role of FeBr3 or FeCl3 in the bromination (Eq. 16.5, p. 751) or chlorination of benzene:

electrophile electrophile nucleophile nucleophile | | R Cl AlCl_ 3 Br Br FeBr_ 3 (16.15c) L 12 L 3 12 L 12 L H H /L /L

complex formation with AlCl3 complex formation with FeBr3 makes Cl a better leaving group makes Br a better leaving group

We’ve learned three general reactions of carbocations: 1. reaction with nucleophiles (Secs. 4.7B–D, 9.6B) 2. rearrangement to other carbocations (Sec. 4.7B) 3. loss of a b-proton to give an alkene (Sec. 9.6B) or aromatic ring (Eq. 16.7, Sec. 16.4A) The reaction of a carbocation with the benzene p electrons is an example of reaction 1. Loss of a proton to chloride ion completes the alkylation.

| R % R HCl AlCl3 (16.15d) / M H Cl AlCl_ 3 vL ++ L Because some carbocations can rearrange, it is not surprising that rearrangements of alkyl groups are observed in some Friedel–Crafts : 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 758

758 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES

the alkyl group has rearranged

CH3 AlCl H CH CH CH CH Cl 3 HCl CH CH CH CH "CHCH CH 3 2 2 2 0 °C 2 2 2 3 2 3 L + ++L L 1-chlorobutane benzene butylbenzene sec-butylbenzene (27% yield) (49% yield) (16.16) In this example, the alkyl group in the sec-butylbenzene product has rearranged. Because pri- mary carbocations are too unstable to be involved as intermediates, it is probably the complex

of the alkyl halide and AlCl3 that rearranges. This complex has enough carbocation character

that it behaves like a carbocation.

1 H 1

| CH3CH2"CHCH2 Cl AlCl_ 3 CH3CH2CHC| H3 Cl AlCl_ 3 (16.17) LL1 3 1 L sec-butyl cation alkylates benzene to give sec-butylbenzene

As we might expect, rearrangement in the Friedel–Crafts alkylation is not observed if the car- bocation intermediate is not prone to rearrangement.

AlCl3 (0.04 equiv.) H (CH3)3C Cl C(CH3)3 (CH3)3C C(CH3)3 HCl L + L L ++LL benzene tert-butylbenzene 1,4-di-tert-butylbenzene (threefold excess) (66% yield) (small amount) (16.18)

In this example, the alkylating cation is the tert-butyl cation; because it is tertiary, this carbo- cation does not rearrange. such as butylbenzene (Eq. 16.16) that are derived from rearrangement- prone alkyl halides are generally not prepared by the Friedel–Crafts alkylation, but rather by other methods that we’ll consider in Secs. 19.12 and 18.10B. Another complication in Friedel–Crafts alkylation is that the alkylbenzene products are more reactive than benzene itself (for reasons discussed in Sec. 16.5B). This means that the product can undergo further alkylation, and mixtures of products alkylated to different extents are observed.

AlCl3 H CH3Cl toluene, , , etc. (16.19) L + (equimolar amounts)

(Notice also the product of double alkylation in Eq. 16.18.) However, a monoalkylation prod- uct can be obtained in good yield if a large excess of the aromatic starting material is used. For example, in the following equation the 15-fold molar excess of benzene ensures that a - cule of alkylating agent is much more likely to encounter a molecule of benzene in the reac- tion mixture than a molecule of the ethylbenzene product. 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 759

16.4 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE 759

AlCl3 H Cl CH2CH3 CH2CH3 (16.20) L + L ethyl chloride benzene ethylbenzene (15-fold excess) (83% yield)

(Notice also the use of excess starting material in Eqs. 16.14 and 16.18.) This strategy is practi- cal only if the starting material is cheap, and if it can be readily separated from the product. Alkenes and can also be used as the alkylating agents in Friedel–Crafts alkylation STUDY GUIDE LINK 16.2 reactions. The carbocation electrophiles in such reactions are generated from alkenes by pro- Different Sources of the Same Reactive tonation and from alcohols by dehydration. (Recall that carbocation intermediates are formed Intermediate in the protonation of alkenes and dehydration of alcohols; Secs. 4.7B, 4.9B, 10.1.)

H SO 2 4 (16.21) 5–10 °C + L benzene cyclohexylbenzene (65–68% yield)

PROBLEMS 16.15 (a) Give a curved-arrow mechanism for the reaction shown in Eq. 16.21. (b) Explain why the same product is formed if is used instead of cyclohexene in this reaction. 16.16 What electrophilic substitution product is formed when 2-methylpropene is added to a large

excess of benzene containing HF and the Lewis acid BF3? By what mechanism is it formed? 16.17 Predict the product of the following reaction and give the curved-arrow mechanism for its formation. (Hint: Friedel–Crafts alkylations can be used to form rings.) (a) AlCl3 H3C CH2CH2CH2 Cl (a compound C10H12 HCl) L L L + (b) AlCl3 CH2CH2CH2CH2 Cl (a compound C10H12 HCl) L L +

F. Friedel–Crafts of Benzene When benzene reacts with an acid chloride in the presence of a Lewis acid such as aluminum

trichloride (AlCl3), a is formed. O O S 1) AlCl3 (1.1 equiv.) S 2) H2O H Cl C CH3 C CH3 HCl (16.22) L + L L L L + benzene (an acid chloride) (a ketone) (97% yield)

This reaction is an example of a Friedel–Crafts acylation (pronounced AY-suh-LAY-shun). In an acylation reaction, an is transferred from one group to another. In the 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:06 AM Page 760

760 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES

Friedel–Crafts acylation, an acyl group, typically derived from an acid chloride, is intro- duced into an aromatic ring in the presence of a Lewis acid. O O S S R C Cl R C L L L L an acid chloride an acyl group The electrophile in the Friedel–Crafts acylation reaction is a carbocation called an acylium

ion. This ion is formed when the acid chloride reacts with the Lewis acid AlCl3. O 1 S3 3 | A ' | RC Cl AlCl3 RRC O CO AlCl_4 (16.23) L L L 1 L 3 acylium ion

Weaker Lewis acids, such as FeCl3 and ZnCl2, can be used to form acylium in Friedel–Crafts of aromatic compounds that are more reactive than benzene. The acylation reaction is completed by the usual steps of electrophilic aromatic substitution (Sec. 16.4B):

O O

|"2 3S3 O MCR C | 3S3 H L C R HCl AlCl (16.24) ) 3 vL"R / H vL L ++

Cl AlCl_ 3 Cl AlCl_ 3 L L As we’ll learn in Sec. 19.6, are weakly basic. Because of this basicity, the ketone product of the Friedel–Crafts acylation reacts with the Lewis acid in a Lewis acid–base asso- ciation to form a complex that is catalytically inactive. This complex is the actual product of the acylation reaction. The formation of this complex has two consequences. First, at least one equivalent of the Lewis acid must be used to ensure its presence throughout the reaction. (No-

tice, for example, that 1.1 equivalent of AlCl3 is used in Eq. 16.22.) This is in contrast to the Friedel–Crafts alkylation, in which AlCl3 can be used in catalytic amounts. Second, the com- plex must be destroyed before the ketone product can be isolated. This is usually accom- plished by pouring the reaction mixture into ice water.

O AlCl3 O| AlCl_ 3 3S3 3SL complex of AlCl3 C R C R with the ketone product L L L L

H2O (16.25)

O 3S3 C R 3HCl Al(OH)3 L L ++ Both Friedel–Crafts alkylation and acylation reactions can occur intramolecularly when the product contains a five- or six-membered ring. (See also Problem 16.17.) 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:07 AM Page 761

16.4 ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS OF BENZENE 761

S Cl C O

L CH S

M 2 1) AlCl3 M M 2) H2O "CH HCl r 2 r + CH2 (16.26) a-tetralone 4-phenylbutanoyl (74–91% yield) chloride

In this reaction, the phenyl ring “bites back” on the acylium ion within the same molecule to form a bicyclic compound. This type of reaction can only occur at an adjacent ortho position because reaction at other positions would produce highly strained products. When five- or six- membered rings are involved, this process is much faster than reaction of the acylium ion with the phenyl ring of another molecule. (Sometimes this reaction can be used to form larger rings as well.) This is another illustration of the proximity effect: the kinetic advantage of intra- molecular reactions (Sec. 11.7B). The multiply substituted products observed in Friedel–Crafts alkylation (Sec. 16.4E) are not a problem in Friedel–Crafts acylation because the ketone products of acylation are much less reactive than the benzene starting material, for reasons discussed in Sec. 16.5B. The Friedel–Crafts alkylation and acylation reactions are important for two reasons. First, the alkylation reaction is useful for preparing certain alkylbenzenes, and the acylation reaction is an excellent method for the synthesis of aromatic ketones. Second, they provide other ways to form carbon–carbon bonds. Here is an updated list of reactions that form carbon–carbon bonds. 1. addition of and to alkenes (Sec. 9.8) 2. reaction of Grignard reagents with and organocuprate reagents with (Sec. 11.4C) 3. reaction of acetylenic anions with alkyl halides or (Sec. 14.7B) 4. Diels–Alder reactions (Sec. 15.3) 5. Friedel–Crafts reactions (Secs. 16.4E and 16.4F)

Charles Friedel and James Mason Crafts The Friedel–Crafts acylation and alkylation (Sec.16.4E) reactions are named for their discoverers,the French chemist Charles Friedel (1832–1899) and the American chemist James Mason Crafts (1839–1917). The two men met in Paris while in the laboratory of Charles Adolphe Wurtz (1817–1884), one of the most famous chemists of that time. In 1877, Friedel and Crafts began their collaborationonthereactionsthatweretobeartheirnames.Friedelsubsequentlybecameaveryac- tive figure in the development of chemistry in France,and Crafts served for a time as president of the Massachusetts Institute of Technology.

PROBLEMS 16.18 Give the structure of the product expected from the reaction of each of the following com-

pounds with benzene in the presence of one equivalent of AlCl3, followed by treatment with water. (a) O (b) O S S (CH3)2CH C Cl C Cl L L L L isobutyryl chloride benzoyl chloride 16_BRCLoudon_pgs4-3.qxd 11/26/08 9:07 AM Page 762

762 CHAPTER 16 • THE CHEMISTRY OF BENZENE AND ITS DERIVATIVES

16.19 Show two different Friedel–Crafts acylation reactions that can be used to prepare the follow- ing compound. ) CH O 3 S C CH3 ccL LL

CH)3

16.20 The following compound reacts with AlCl3 followed by water to give a ketone A with the for- mula C10H10O. Give the structure of A and a curved-arrow mechanism for its formation. O S H3C CH2CH2 C Cl L L L L

ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS 16.5 OF SUBSTITUTED

A. Directing Effects of When a monosubstituted benzene undergoes an electrophilic aromatic substitution reaction, three possible disubstitution products might be obtained. For example, nitration of bromoben- zene could in principle give ortho-,meta-, or para-bromonitrobenzene. If substitution were totally random, an ortho:meta:para product ratio of 2 : 2 :1 would be expected. (Why?) It is found experimentally that this substitution is not random, but is regioselective. Br Br Br Br

" " NO2 " " HNO 3 M (16.27) i i ++i i M NO2 bromobenzene o-bromonitrobenzene "NO2 m-bromonitrobenzene (36%) (2%) p-bromonitrobenzene (62%) Other electrophilic substitution reactions of bromobenzene also give mostly ortho and para . If a substituted benzene undergoes further substitution mostly at the ortho and para positions, the original is called an ortho, para-directing group. Thus, bromine is an ortho, para-directing group, because all electrophilic substitution reactions of bromoben- zene occur at the ortho and para positions. In contrast, some substituted benzenes react in electrophilic aromatic substitution to give mostly the meta disubstitution product. For example, the bromination of nitrobenzene gives only the meta . NO2 NO2 " " Br 2 (16.28) FeBr3 i heat i M Br nitrobenzene m-bromonitrobenzene (only product observed) Other electrophilic substitution reactions of nitrobenzene also give mostly the meta isomers. If a substituted benzene undergoes further substitution mainly at the meta position, the origi-