15597.eh16.291-30311/3/0510:02Page291 EQA 16 Electrophilic Attack on Derivatives of Benzene: Substituents Control Regioselectivity s on the characteristics. Outline of the Chapter 16-1 Activation or Deactivation by Substituents on the Benzene Ring 16-2 Directing Inductive Effects of Alkyl Groups 16-3 Effects of Substituents in Conjugation with the Benzene Ring 16-4 Electrophilic Attack on Disubstituted Benzenes Effects of substituents on the reactivity and regioselectivity of further electrophilic substitution ona benzene ring. 16-5 Synthetic Strategies General principles and useful new reactions. 16-6 16-7 Polycyclic Aromatic Hydrocarbons and Cancer Keys to the Chapter3 16-1 through 16-3.Directing Effects:Activation and Deactivation Don't forget the basics:Electrophiles seek electrons!So.reactivity of a benzene ring toward electrophiles that dona t which sub h I 39
16 Electrophilic Attack on Derivatives of Benzene: Substituents Control Regioselectivity The preceding chapter introduced you to the properties and chemistry of benzene itself. In this chapter the chemistry is expanded to include several new reactions not only of benzene but also of derivatives of benzene containing various substituents. The text focuses on the effects of substituents on the chemistry of the benzene ring. The first and rate-determining step of electrophilic substitution is the formation of a delocalized cation. Different types of substituents can affect the stability of this cation and make its formation easier or harder. Substituents on the ring also direct the attack of an electrophile to specific positions. This study guide chapter contains information that may help you avoid a lot of memorization. You will see that the effect of a substituent on benzene chemistry can be predicted from a relatively straightforward examination of its electronic characteristics. Outline of the Chapter 16-1 Activation or Deactivation by Substituents on the Benzene Ring 16-2 Directing Inductive Effects of Alkyl Groups 16-3 Effects of Substituents in Conjugation with the Benzene Ring 16-4 Electrophilic Attack on Disubstituted Benzenes Effects of substituents on the reactivity and regioselectivity of further electrophilic substitution on a benzene ring. 16-5 Synthetic Strategies General principles and useful new reactions. 16-6 Reactivity of Polycyclic Benzenoid Aromatics What happens when two or more benzene rings are fused together. 16-7 Polycyclic Aromatic Hydrocarbons and Cancer Keys to the Chapter3 16-1 through 16-3. Directing Effects: Activation and Deactivation Don’t forget the basics: Electrophiles seek electrons! So, reactivity of a benzene ring toward electrophiles will be enhanced by substituents that donate electron density to the ring, and it will be reduced by substituents that withdraw electron density from the ring. “Reactivity” in this context is the rate at which substitution occurs, which is determined by the rate-determining step—electrophilic attack to form a carbocation. Electron-donating 291 1559T_ch16_291-303 11/3/05 10:02 Page 291
1559T_ch16_291-30311/3/0510:02Page292 ⊕ EQA 292 Chapter 16 ELECTROPHIUC ATTACK ON DERIVATIVES OF BENZENE:SUBSTITUENTS CONTROL REGIOSELECTIVITY s)will stabilize the cation.lowerine the transition stat for its formation an and electron-withdrawing groups(d nore,thes Both inductive and resonance effects are involved.The favored reaction proceeds through the most stabi lizedorleastd lized)intermediate carbocation.Study carefully the resonand ce foms pictured for the po fall in theifler cae in Table 1-1.paicc the one s that 1.All substituents with lone pairs on the atom attached to the be 2.Al substitucnts that havepositively porized(atom lackinga lon pair attached tothe ben ring are meta directors. These generalizations always hold and can be used as aids to help you remember whether a group belongs in one category or the other. 16-5.Synthetic Strategies This on as a para 16-6.Reactivity of Polycyclic Ben id Ar Fused polycyclics such as naphthalene,antracene,and phennthrene exhibit both similarities and difference .Ir the rings are not identically substituted.reaction occurs at the most activated ring.Substituents have the same di- which rule of thumb.additions occ in such a way as to p in benzene rings as muc eSoddiions to both nhace and phenantenet thpositionsleavingwo simple Solutions to Problems 28.Order of decreasing reactivity:for brevity,only the substituents are listed (a) ingly e (b)-O-Na+>-OCH,>-OCCH3.Resonance activators.Compare the availability of oxygen's on they activate therin onation to stabili e the cationic second best.and the oxygen in the ester orst because it is attached to acarbonyl cabon that pulls the electrons away from the ring. (e)-CH2CHa>-CH.CCla>-CH2CF3>-CF2CH3.Inductive effects again.combined with dis tance to ring. 29.Activated:(c),(d).(e).(g)
292 • Chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE: SUBSTITUENTS CONTROL REGIOSELECTIVITY groups (activating groups) will stabilize the cation, lowering the transition state energy for its formation and speeding up the reaction, and electron-withdrawing groups (deactivating groups) will do just the opposite. Furthermore, these effects will differ at different positions around the ring relative to the location of the substituents already present, giving rise to directing effects. Both inductive and resonance effects are involved. The favored reaction proceeds through the most stabilized (or least destabilized) intermediate carbocation. Study carefully the resonance forms pictured for the possible cations derived from electrophilic attack on methylbenzene and (trifluoromethyl)benzene (Section 16-2), and on benzenamine (aniline), benzoic acid, and a halobenzene (Section 16-3). Notice the types of groups that fall into the different categories in Table 16-1. In particular, notice the following two general trends: 1. All substituents with lone pairs on the atom attached to the benzene ring are ortho, para directors. 2. All substituents that have a positively polarized () atom lacking a lone pair attached to the benzene ring are meta directors. These generalizations always hold and can be used as aids to help you remember whether a group belongs in one category or the other. 16-5. Synthetic Strategies This section shows how to plan syntheses of multiply substituted benzenes. It also illustrates the interconversion of NH2 and NO2, reduction of CPO to CH2, use of SO3H as a para-blocking group, and several other valuable synthetic “tricks.” 16-6. Reactivity of Polycyclic Benzenoid Aromatics Fused polycyclics such as naphthalene, anthracene, and phenanthrene exhibit both similarities and differences with respect to benzene. For example, electrophilic aromatic substitution occurs but is generally easier with the polycyclics and proceeds with milder reagents. The activation energies for attack are lower because the intermediate cations are more highly delocalized (more resonance forms!) and, therefore, lower in energy. If the rings are not identically substituted, reaction occurs at the most activated ring. Substituents have the same directing and activating/deactivating effects you saw with benzene. Fused polycyclics also have an increased tendency to undergo addition reaction, which are rare for benzene itself. As a general rule of thumb, additions occur in such a way as to preserve intact benzene rings as much as possible. So, additions to both anthracene and phenanthrene occur at the 9,10 positions, leaving two simple benzene rings intact. Solutions to Problems 28. Order of decreasing reactivity; for brevity, only the substituents are listed. (a) OCH3 OCH2Cl OCHCl2 OCCl3. Electronegative Cl’s make carbon , so the inductive effect becomes increasingly electron withdrawing and deactivating. O B (b) OO Na OOCH3 OOCCH3. Resonance activators. Compare the availability of oxygen’s lone pair electrons, because they activate the ring by resonance donation to stabilize the cationic intermediate. The negatively charged oxygen atom is the best donor, the neutral ether oxygen second best, and the oxygen in the ester worst because it is attached to a carbonyl carbon that pulls the electrons away from the ring. (c) OCH2CH3 OCH2CCl3 OCH2CF3 OCF2CH3. Inductive effects again, combined with distance to ring. 29. Activated: (c), (d), (e), (g) 1559T_ch16_291-303 11/3/05 10:02 Page 292
1559r.ah16.291-30311/3/0510:02Page293 EQA Soutions to Problems293 COOH COOH In each series of cor unde the hen e rina ted the onewith wo carbonyl group substituentsis most deactivated.and the of eachis intermediate. 31.The two ethyl substituents in 1 3-din other' ubly activated fo to different carbon n theing For 1-dimethy benzene.the methyl positions 4 and 6. while the methyl group at C2 directs to positions 3 and 5 H More stah More ociatedwithisfopiliCn either 12-or 14-dimethyibenze e are directly stabilized by more than one of the methyl groups.They are all higher in energy,and their formation requires surmounting a larger activation barrier CH CH 32.a) + b)1 + SO-H CH
Solutions to Problems • 293 30. (a) (b) In each series of compounds, the benzene ring with two alkyl group substituents is most activated, the one with two carbonyl group substituents is most deactivated, and the one with one of each is intermediate. 31. The two methyl substituents in 1,3-dimethylbenzene reinforce each other’s activating and directing effects: They both direct subsequent electrophilic attack to positions 4 and 6 on the ring. For example, position 4 is ortho to the methyl group at C3 and para to the methyl group at C1, so it is doubly activated for subsequent substitution. In either 1,2- or 1,4-dimethylbenzene (o- or p-xylene) the two methyl groups direct to different carbons in the ring. For example, in 1,2-dimethylbenzene, the methyl group at C1 directs to positions 4 and 6, while the methyl group at C2 directs to positions 3 and 5. Another way of looking at the situation is to notice that the intermediate cation resulting from attack at C4 on 1,3-dimethylbenzene has two resonance contributors in which the cationic carbon is methyl-substituted: Therefore the energy of this cation is lower, and the activation barrier associated with its formation is reduced. Its formation is relatively fast. In contrast, none of the cations derived from electrophilic attack on either 1,2- or 1,4-dimethylbenzene are directly stabilized by more than one of the methyl groups. They are all higher in energy, and their formation requires surmounting a larger activation barrier. 32. (a) (b) (c) (d) C(CH3)3 C(CH3)3 SO3H SO3H C(CH3)3 C(CH3)3 NO2 NO2 CH3 SO3H CH3 SO3H CH3 NO2 CH3 NO2 CH3 CH3 E H CH3 CH3 E CH3 CH3 H E CH3 CH3 H E More stable More stable > > O O O CH3 CH3 > COOH CH3 > COOH COOH 1559T_ch16_291-303 11/3/05 10:02 Page 293
1559T_ch16_291-30311/3/0510:02Page294 ⊕ EQA 294.Chapter 16 ELECTROPHIUC ATTACK ON DERIVATIVES OF BENZENE:SUBSTITUENTS CONTROL REGIOSELECTIVITY Changing m a small (methyl g para-disubstituted products. s is determined by the directing effect of the substit t that is 式69 34.Ortho attack 6-心-5 反 6--6- There are no resonanc forms with+adjacent tosulfur when attack occurs me
Changing from a small (methyl) group to a very bulky (1,1-dimethylethyl) substituent will strongly sterically inhibit ortho substitution. Reactions (c) and (d) give rise to almost entirely para-disubstituted products. 33. The position at which substitution occurs is determined by the directing effect of the substituent that is already present in the starting compound. Methoxy and chloro are ortho, para-directing groups. Most of the time they direct incoming electrophiles to the para position, especially if the electrophile is somewhat bulky, as is the case in (a) and (d). Nitro and carboxylic acid are meta-directing. (a) (b) (c) (d) 34. Ortho attack: Para attack: Meta attack: There are no resonance forms with adjacent to sulfur when attack occurs meta. SO3H E SO3H E H SO3H SO3H E E H H SO3H E SO3H SO3H E H Especially bad E H SO3H E H SO3H E SO3H E H SO3H E H S OH O O E H Especially bad Cl C O CH3 CO2H NO2 NO2 Br OCH3 SO3H 294 • Chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE: SUBSTITUENTS CONTROL REGIOSELECTIVITY 1559T_ch16_291-303 11/3/05 10:02 Page 294
1559Tch16291-30311/3/0510:02Page295 Solutions to Problems295 position. examining the st ance form s.of the carbocatio of the benzen (a) can dr for benzene top three forms in the brackets below.Howeve having del lized the positive c 8-288 8-8-8 ween the incapable of providing additional resonance stabilization beyond that of the three original forms present in the ring on uon took place 88&8 mitting three more resonance forms to participate in stabilizing the intermediate.(The second and forms in the bottom group of three
Solutions to Problems • 295 35. Statement is correct. All meta-directors deactivate the entire ring by inductive electron withdrawal. Deactivation at the ortho and para positions is most intense as a result of resonance (see, for example, the answer to Problem 34). Meta substitution occurs only because the deactivation is felt least strongly at that position. 36. Solve the problem by examining the structures, in particular the resonance forms, of the carbocation that is produced by attachment of a generic electrophile, E, to each of the three possible positions on one of the benzene rings: ortho, meta, and para, with respect to the other ring. Use principles developed in this chapter to evaluate the relative stabilities of these carbocations. The more stable carbocations should form faster and will determine the major product(s). (a) Substitution ortho: attach the electrophile to either ring (they are equivalent), at the position adjacent to the bond connecting the two rings. Initially, we see the same three resonance forms that we can draw for substitution on benzene itself—the top three forms in the brackets below. However, having delocalized the positive charge to the position of attachment of the second ring (top right), we can continue to use the double bonds of this ring to delocalize further, giving us three more resonance forms (bottom three in brackets), for a total of six. (b) Substitution meta: attach the electrophile one position further removed from the bond between the rings, the meta position. Draw the resonance forms for the carbocation. Notice now that the positive charge is no longer delocalized to the position of attachment to the second ring. This ring is incapable of providing additional resonance stabilization beyond that of the three original forms present in the ring on which the substitution took place. (c) Substitution para: attach the electrophile and proceed as before. As was the case for substitution ortho, one of the three initial forms places the positive charge at the ring connection position, permitting three more resonance forms to participate in stabilizing the intermediate. (The second and third resonance forms in the top group of three have been written in reverse order—and the electron-pushing arrows modified accordingly—so that the form at the right leads naturally to the three forms in the bottom group of three.) E H E H E H E E H H H H H H E EEE E E 1559T_ch16_291-303 11/3/05 10:02 Page 295