1559T_ch16_291-30311/3/0510:02Pa9e291 EQA 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 try is expan of the rent types s cation and make mation easier contninformion thatmayhelp youv omemoroYouethat theefeutte 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 ring. 16-5 Synthetic Strategies General principles and useful new reactions. 16-7 Polycyclic Aromatic Hydrocarbons and Cancer Keys to the Chapter3 16-1 through 16-3.Directing Effects:Activation and Deactivation ctrons:so,rea on density from the ring."React trophilic attack to form a carbocation.Electron-donating 291
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
1559Tch16291-30311/3/0510:02Page292 EQA 292 chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE SUBSTITUENTS CONTROL REGIOSELECTIVITY groups (a hermore.these effe ctswfrrotioroudheringrelativetothection ofthe ent,givi tne6163Nep器 ring are meta directors. nc ways hold and ca n be used as aids to help you remember whether a group belong gor or the other 16-5.Synthetic Stre ateaies This sectic shows how to plan syntheses of multiply substituted benzenes.It also illustrates the interconver iNnNeduction of C to CHa.use of SOH as a para-blocking group.and several other 1-.ivy of Arom nd dif with respect to benzene.For example.electrophilic aromatic substitution occurs but is generally easier with the milder reagents.The activation en nergies for attack are ower because the inte recting and activating/deactivating effects you saw with benzene. d polycyclics also h e an inc sed tendency to undergo addition reaction,which are rare for benzen an and phennthree thevmgimple benzene rings intact. Solutions to Problems 28.Order of decreasing reactivity:for brevity.only the substituents are listed (a) CH3>-CH2CI >-CHCl2>-CCls.Electronegative Cl's make carbon 8*,so the inductive effect becomes increasingly electron withdrawing and deactivating. 0 (b)-O-Na>-OCH3 >-OCCH3.Resonan that g CHCHCHCCl,nductive effectsaain,combined with 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
1559T_ch16_291-30311/3/0510:02Page293 EQA Soutionso Problems293 6 .cc.c.c two methyl substituents in 1.3-dimethylbenzene reinforce each other's activan s:They subsequen itions ier1-dimethyibenzene ()the on 1.3-dimethylbenzene has wo resonance contributors in which the cationic carbon is methyl-substituted: CH CH CH CH CH th and the activation ba d with ite ormation requires surmounting a larger activat 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
1559r_ch16.291-3031/3/0510:02Page294 294.chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE SUBSTITUENTS CONTROL REGIOSELECTIVITY para-disubstituted products. 33. as is the case in (a)and (d).Nitro and carboxylic acid are meta-directing. Ortho attac ⊕ 乐心 顺这 Meta attack 5、--5- There are no resonance forms with adiacent to 8 sulfur when attack occurs met
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
al s B.2.8 8 3388
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
Additional resonance forms provide additional stabilization, and therein lies the answer. Substitution either ortho or para leads to a carbocation delocalized throughout both rings, with a total of six resonance forms, while meta substitution gives a cation limited to delocalization in only one of the rings, with only three contributing resonance forms. The meta cation is less stable, higher in energy, requires surmounting a higher activation energy barrier to form, and therefore forms more slowly. The phenyl ring as a substituent is thus an ortho, para-directing group with respect to electrophilic aromatic substitution. It is also activating, again a consequence of the additional stabilization of the cation formed upon ortho or para substitution, relative to the cation formed from substitution on benzene itself. 37. Where both ortho and para products are formed, the para is generally the major one. (a) (b) (c) (d) (e) (f) NO2 NO2 OCH3 OCH3 SO2Cl SO2Cl CH(CH3)2 (CH3)2CH SO3H SO3H C NO2 O CH2CH3 Cl Cl Br Br C N(CH3)2 (CH3)2N O CH3 C CH3 O E E H E H E H E H E H E H 296 • Chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE: SUBSTITUENTS CONTROL REGIOSELECTIVITY 1559T_ch16_291-303 11/3/05 10:02 Page 296
1559T_ch16_291-30311/3/0510:02Page297 ⊕ EQA Soutionso Problems97 exists. (i)No reaction.Friedel-Crafts reaction does not occur on rings containing meta-directing groups:The ring is too deactivated. 39.(a)Activation effects are additive.1.3-Dimethylbenzene (m-xylene)differs from its 1.2 and 1.4
Solutions to Problems • 297 38. Orientation of reaction is determined by more activating (or less deactivating) substituent (marked in each case below). Again, the para product can be expected to predominate where a choice of ortho or para exists. (a) (b) (c) (d) (e) (f) (g) (h) (i) No reaction. Friedel-Crafts reaction does not occur on rings containing meta-directing groups: The ring is too deactivated. 39. (a) Activation effects are additive. 1,3-Dimethylbenzene (m-xylene) differs from its 1,2 and 1,4 isomers because it is the only one that contains ring positions activated by both methyl substituents. Electrophilic substitution at C2, C4, and C6 (which is equivalent to C4) gives intermediate cations NHCOCH3 NO2 Cl NO2 NO2 NO2 NO2 Para to this Ortho to this The saturated ring is not special. Treat it just like two alkyl groups. OCH3 HO3S CH3 CCH3 NO2 SO3H Br O (Both meta directing) NHCOCH3 CH3 Br NHCOCH3 CH3 Br COOH NO2 CH3CH2 COOH NO2 CH3CH2 Cl SO3H Cl CH3 Cl NO2 CH3 NO2 CH3 1559T_ch16_291-303 11/3/05 10:02 Page 297
1559r_ch16.291-3031/3/0510:02Page298 298 chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE SUBSTITUENTS CONTROL REGIOSELECTIVITY round the ring.Fo CH; The cations are more stable.the transition states leading to them are lower in energy.and they form faster.Substitution mainly occursat C4/6(C2 is a sterically hindered position because of the yourself that electrophilic substitution on the ortho and para isomers cannot lead to such a doubly stabilized intermediate cation. b) open position. 1.3.5 isomr and the other two is quitearge about factor of 200 inae 40.Friedel-Crafts reactions are understood to be followed by H'HOwork-up (a)1.CH CH-CL.AlCh:2.CH COCI.AICh (b)1.HNO3,H2SO:2.Cl2.FeCla (e)1.CHCOCI,AICls:2.SO3.HSO Can't do it in the reverse order.The Friedel-Crafts reaction fails with the SOH group there. (d)1.HNO3.H2SO:2.HCl,Zn(Hg):3.SO3.H2SO.heat:4.CF;CO,H (e)1.Cl2.FeCly:2.excess conc.HNO3.HSO.A (f)1.Bra.FeBrs:HNO3.HSO separate para from ortho .C.○N 4.Cl2.CHCl.OC(chlorinates once,ortho to NH2:see Section 16-3):5.CF CO H (g)1.Bra.FeBra:.SO3.HaSO(blocks para):3.Cla.FeCls:4.HO. (h)1.CHaCl,AlCla:2.SOa.H2SO:3.excess Br2.FeBra:4.H2O.A
whose positive charges are delocalized to two methyl-substituted positions around the ring. For attack at C4, you have The cations are more stable, the transition states leading to them are lower in energy, and they form faster. Substitution mainly occurs at C4/6 (C2 is a sterically hindered position because of the methyls on either side). You should check for yourself that electrophilic substitution on the ortho and para isomers cannot lead to such a doubly stabilized intermediate cation. (b) Three methyl groups, but the principle to be applied is the same: Look for positions that are doubly or triply activated. In each structure count up the number of methyls ortho or para to each open position. The last should be the most reactive toward electrophiles: Each vacant position is activated by being ortho or para to all three methyl groups. By the way, the reactivity difference between the 1,3,5 isomer and the other two is quite large, about a factor of 200 in rate. 40. Friedel-Crafts reactions are understood to be followed by H, H2O work-up. (a) 1. CH3CH2Cl, AlCl3; 2. CH3COCl, AlCl3 (b) 1. HNO3, H2SO4; 2. Cl2, FeCl3 (c) 1. CH3COCl, AlCl3; 2. SO3, H2SO4 Can’t do it in the reverse order. The Friedel-Crafts reaction fails with the SO3H group there. (d) 1. HNO3, H2SO4; 2. HCl, Zn(Hg); 3. SO3, H2SO4, heat; 4. CF3CO3H (e) 1. Cl2, FeCl3; 2. excess conc. HNO3, H2SO4, (f) 1. Br2, FeBr3; 2. HNO3, H2SO4, separate para from ortho; 3. HCl, Zn(Hg) 4. Cl2, CHCl3, 0°C (chlorinates once, ortho to NH2; see Section 16-3); 5. CF3CO3H (g) 1. Br2, FeBr3; 2. SO3, H2SO4 (blocks para); 3. Cl2, FeCl3; 4. H2O, (h) 1. CH3Cl, AlCl3; 2. SO3, H2SO4; 3. excess Br2, FeBr3; 4. H2O, makes Br NH2 ; CH3 CH3 1 2 2 CH3 CH3 1 2 CH3 2 CH3 3 3 CH3 3 CH3 CH3 E H E Major contributors to the resonance hybrid CH3 CH3 6 2 4 CH3 CH3 CH3 CH3 H E CH3 H E CH3 298 • Chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE: SUBSTITUENTS CONTROL REGIOSELECTIVITY 1559T_ch16_291-303 11/3/05 10:02 Page 298
1559T_ch16_291-30311/3/0510:02Page299 EQA Solutions to Problems.299 CHO CH-O ,CH,0° C MgC performed on biphenyl cannot serve asn enry to the preparation of thi important compound 43.(a)NMR shows two sets of benzene hydrogens ina:3 integration ratio,and the IR bands at685 and 735 cmindicate a monos bstituted benzene.This analysis leads to the only logical answe bromobenzene,CHsBr, -Br,which is made from benzene +Bra and FeBrs. ehre2g的bu un?0 pta议cartons C NH- 的位 is in the range for ortho disubstituted rings. (d)Similar.but the NMR(two doublets,each 2H)and the IR(80cm)indicate that this is the 》〉-NH Aum any orhprmtures can be readily separated to give the para product
Solutions to Problems • 299 41. 42. The synthesis of URB597 was extremely challenging, more so for the positions of its substituents than for their structure. Both groups are located in meta positions relative to the bond between the rings. Problem 36 revealed that phenyl rings as substituents are ortho, para directing. Therefore electrophilic aromatic substitution reactions performed on biphenyl cannot serve as an entry to the preparation of this important compound. 43. (a) NMR shows two sets of benzene hydrogens in a 2 : 3 integration ratio, and the IR bands at 685 and 735 cm1 indicate a monosubstituted benzene. This analysis leads to the only logical answer, bromobenzene, C6H5Br, which is made from benzene Br2 and FeBr3. (b) NMR shows three benzene hydrogens, a 1 H triplet and a 2 H doublet; what you would expect for three hydrogens in adjacent positions around a ring, with the end ones equivalent: CHOCHOCH. What else is there? A 2 H lump at 4.5 ppm together with two bands in the IR at 3382 and 3478 cm1 strongly suggest an NH2 group. How about an atom count? You’re up to six carbons for the benzene ring, five H and an N. The only formula that will fit is C6H5Br2N. Putting the NH2 on the benzene ring and then attaching the two Br’s one each side of it fits the data: 2,6-dibromobenzenamine is the answer. (c) The NH2 is again present, but the NMR now shows four benzene hydrogens in a complicated pattern. The IR helps: The band at 745 cm1 is in the range for ortho disubstituted rings. 2-Bromobenzenamine is the answer: C6H6BrN. (d) Similar, but the NMR (two doublets, each 2 H) and the IR (820 cm1 ) indicate that this is the para isomer of C: 4-bromobenzenamine: Synthesis. (Assume any ortho para mixtures can be readily separated to give the para product in good yield.) Br NH2 Br NH2 Br Br H NH2 H H Br, CH3O Cl CH3O CH3O MgCl anisyl alcohol Cl2, CHCl3, 0° Mg, THF 1. HCHO 2. H, H2O 1559T_ch16_291-303 11/3/05 10:02 Page 299
1559r.ah16.291-30311/3/0510:02Page300 300 chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE SUBSTITUENTS CONTROL REGIOSELECTIVITY A0. D 0.H ai).C S0.HS0 HO.S NH ⊕ 4◇+4c○ Although aromatic.naphthalene does undergo some addition reactions like this one.Addition occurs in such a way that one aromatic benzene ring is left fully intact. 45.Reaction should occur on the most activated (or least dea ted by the groups present CH3 CH:O CH:C is sterically hindered o.c
44. Although aromatic, naphthalene does undergo some addition reactions like this one. Addition occurs in such a way that one aromatic benzene ring is left fully intact. 45. Reaction should occur on the most activated (or least deactivated) ring, directed by the groups present. (a) (b) Major: is sterically hindered (c) NO2 NO2 3 5 CH3O NO2 ) )Cl CH3O NO2 Cl CH3 CH3 NO2 Pd-C 2H2 Br2, FeBr3 H, H2O, Removes SO3H B Br HO3S Br NH2 SO3, H2SO4 Blocks position para to amine (again) A C Br HO3S NH2 SO3, H2SO4 1. HNO3, H2SO4 2. H2 Ni H2O, Removes SO3H Br A C SO3H Br SO3H NH2 mainly 1. HNO3, H2SO4 A D 2. H2 Ni 300 • Chapter 16 ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE: SUBSTITUENTS CONTROL REGIOSELECTIVITY 1559T_ch16_291-303 11/3/05 10:02 Page 300