Chapter 16 - modi (3)_fd21be09e654c809905a1d06f436e30a PDF

16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6th edition, Chapter 16 ©2003 Ronald Kluger Department of Chemistry University of Toronto  Substitution Reactions of Benzene and Its Derivatives Benzene is aromati...

16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6th edition, Chapter 16 ©2003 Ronald Kluger Department of Chemistry University of Toronto  Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated compound with 6  electrons Reactions of benzene lead to the retention of the aromatic core Electrophilic aromatic substitution in which an electrophile (E+) reacts with an aromatic ring and substitutes for one of the hydrogens. Replaces a proton on benzene with another electrophile 2  16.1 Bromination of Aromatic Rings Benzene’s  electrons participate as a Lewis base in reactions with Lewis acids The product is formed by loss of a proton, which is replaced by bromine In electrophilic alkene additions 3 4 16.1 Electrophilic Aromatic Substitution Reactions: Bromination Aromatic rings are less reactive toward electrophiles than alkenes. For example, Br2 in CH2Cl2 solution reacts instantly with most alkenes but does not react with benzene at room temperature. A catalyst such as FeBr3 is needed. The catalyst makes the Br2 molecule more electrophilic by polarizing it to give an FeBr4-Br+ species that reacts as if it were Br+. 5  Addition Intermediate in Bromination The addition of bromine occurs in two steps In the first step the  electrons act as a nucleophile toward Br2 (in a complex with FeBr3) This forms a cationic addition intermediate from benzene and a bromine cation The intermediate is not aromatic carbocation and therefore high in energy. 6  Formation of Product from Intermediate The cationic addition intermediate transfers a proton to FeBr4- (from Br- and FeBr3) This restores aromaticity (in contrast with addition in alkenes) 7  16.2 Other Aromatic Substitutions The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles The cationic intermediate was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate George Willard Wheland 1907-1974 8  Aromatic (Halogenation) Chlorination and Iodination Chlorine and iodine (but not fluorine, which is too reactive and only poor yields of mono fluoroaromatic products are obtained by direct fluorination) can produce aromatic substitution with the addition of other reagents to promote the reaction. Chlorination requires FeCl3 catalyst. Iodine itself is unreactive toward aromatic rings, so an oxidizing agent such as hydrogen peroxide or a copper salt such as CuCl2 must be added to the reaction. Iodine must be oxidized to form a more powerful I + species (with Cu+ or peroxide) 9  Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO 2+ (nitronium ion) The reaction with benzene produces nitrobenzene protonation 10  Aromatic Sulfonation Substitution of H by SO3 (sulfonation) Reaction with a mixture of fuming sulfuric acid and SO 3 Reactive species is sulfur trioxide or its conjugate acid Reaction occurs via Wheland intermediate and is reversible depending on the reaction conditions. 11  (Aromatic Hydroxylation) Alkali Fusion of Aromatic Sulfonic Acids Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol) is difficult and rarely done Sulfonic acids are useful as intermediates Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO3H group with an OH Example is the synthesis of p-cresol 12 4-methylphenol  16.3 Alkylation of Aromatic Rings: The Friedel– Crafts Reaction Aromatic substitution of a R+ for H Aluminum chloride promotes the formation of the carbocation Wheland intermediate forms 13  Limitations of the Friedel-Crafts Alkylation Only alkyl halides can be used (F, Cl, I, Br) Aryl halides and vinylic halides do not react (their carbocations are too hard to form) because aryl and vinylic carbocations are too high in energy to form under Friedel–Crafts conditions. 14 Friedel–Crafts reactions don’t succeed on aromatic rings that are substituted either by a strongly electron-withdrawing group (deactivating group) such as carbonyl (C=O) or by a basic amino group that can be protonated. 15  Control Problems A third limitation is multiple alkylations can occur because the first alkylation is activating, it’s often difficult to stop the reaction after a single substitution. A high yield of monoalkylation product is obtained only when a large excess of benzene is used. 16 Carbocation Rearrangements During Alkylation It is the final limitation Similar to those that occur during electrophilic additions to alkenes Can involve Hydride or alkyl shifts Particularly when a primary alkyl halide is used. 17 18  Acylation of Aromatic Rings Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, COR Benzene with acetyl chloride yields acetophenone  Acylations never occur more than once on a ring because the product acylbenzene is less reactive than the nonacylated starting material. 19  Mechanism of Friedel-Crafts Acylation Similar to alkylation and the same limitations Reactive electrophile: resonance-stabilized acyl cation An acyl cation does not rearrange because of the resonance stabilization of the charge. 20 21 22 16.4 Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or (much) less reactive than benzene Substituents affect the orientation of the reaction – the positional relationship is controlled ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators 23  Substituents affect the reactivity of the aromatic ring. Some substituents activate the ring, making it more reactive than benzene, and some deactivate the ring, making it less reactive than benzene. In aromatic nitration, for instance, an OH substituent makes the ring 1000 times more reactive than benzene, while an - NO2 substituent makes the ring more than 10 million times less reactive. 24  Substituents affect the orientation of the reaction. The nature of the substituent initially present on the benzene ring determines the position of the second substitution. An -OH group directs substitution toward the ortho and para positions, for instance, while a carbonyl group such as -CHO directs substitution primarily toward the meta position 25 Predict the major product of the sulfonation of toluene. 26 27  Activating and Deactivating Effects Activating groups is that they donate electrons to the ring, thereby making the ring more electron-rich, stabilizing the Wheland carbocation intermediate, and lowering the activation energy for its formation. Deactivating groups is that they withdraw electrons from the ring, thereby making the ring more electron-poor, destabilizing the carbocation intermediate, and raising the activation energy for its formation. 28 29  Origins of Substituent Effects An interplay of inductive effects and resonance effects Inductive effect - withdrawal or donation of electrons through a s bond due to electronegativity Halogens, hydroxyl groups, carbonyl groups, cyano groups, and nitro groups 30  Inductive Effects This effect is most pronounced in halobenzenes and phenols, in which the electronegative atom is directly attached to the ring But is also significant in carbonyl compounds, nitriles, and nitro compounds, in which the electronegative atom is farther removed. Halogens, C=O, CN, and NO2 withdraw electrons through sigma bond connected to ring Controlled by electronegativity and the polarity of bonds in functional groups Alkyl groups donate electrons 31  Resonance Effects – Electron Withdrawal. Resonance effect - withdrawal or donation of electrons through a pi bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring. C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance  electrons flow from the rings to the substituents. Leaving a positive charge in the ring. Substituents with an electron-withdrawing resonance effect have the general structure –Y=Z, where the Z atom is more electronegative than Y. 32  Resonance Effects – Electron Donation Halogen, OH, alkoxyl (OR), and amino substituents donate electrons  electrons flow from the substituents to the ring Effect is greatest at ortho and para Lone-pair electrons flow from the substituents to the ring, placing a negative charge on the ring. Substituents with an electron-donating resonance effect have the following general structure where the Y atom has a lone pair of electrons available for donation to the ring. 33  Contrasting Effects Halogen, hydroxyl, alkoxyl, and amino substituents, for instance, have electron-withdrawing inductive effects because of the electronegativity of the -X, -O, or -N atom bonded to the aromatic but have electron-donating resonance effects because of the lone-pair electrons on those -X, -O, or -N atoms. 34  When the two effects act in opposite directions, the stronger one dominates. Thus, hydroxyl, alkoxyl, and amino substituents are activators because their stronger electron-donating resonance effect outweighs ‫ يفوق‬their weaker electron-withdrawing inductive effect. Halogens, however, are deactivators because their stronger electron withdrawing inductive effect outweighs their weaker electron-donating resonance effect. 35  Ortho- and Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions ortho and para to themselves Alkyl group is most effective in the ortho and para positions 36  Although all three intermediates are resonance-stabilized, the ortho and para intermediates are more stabilized than the meta intermediate. A resonance form places the positive charge directly on the methyl-substituted carbon, where it is in a tertiary carbon position rather than secondary carbon and can be stabilized by the electron-donating inductive effect of the methyl group. The ortho and para intermediates are thus lower in energy than the meta intermediate and form faster. 37  Ortho- and Para-Directing Activators: OH and NH2 Hydroxyl, alkoxyl, and amino groups are ortho–para activators. Because they have a strong, electron-donating resonance effect Most pronounced at the ortho and para positions 38  The ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms including one particularly favorable form that involves electron donation from the oxygen atom. The favorable form that allows the positive charge to be stabilized by electron donation from the substituent oxygen atom. 39 Ortho- and Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate because of electron donation of the halogen lone-pair electrons. each atom possesses a complete octet of electrons. 40  Meta-Directing Deactivators Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by deactivation from carbocation intermediate Resonance in ortho and para cannot produce stabilization 41  The meta intermediate has three favorable resonance forms, whereas the ortho and para intermediates have only two. In both ortho and para intermediates, the third resonance form is unfavorable because it places the positive charge directly on the carbon that bears the aldehyde group, where it is disfavored by a repulsive interaction with the positively polarized carbon atom of the C=O group. In general, any substituent that has a positively polarized atom (carbon atom of the carbonyl) directly attached to the ring will make one of the resonance forms of the ortho and para intermediates unfavorable and will thus act as a meta director. 42 Summary Table: Effect of Substituents in Aromatic Substitution 43 16.5 Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive both the methyl and the nitro group direct further substitution to the same position (ortho to the methyl = meta to the nitro). A single product is thus formed on electrophilic substitution. 44  Substituents with Opposite Effects If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome Usually gives mixtures of products -OH is a more powerful activator than -CH3. 45 Meta-Disubstituted Compounds Are Unreactive Further substitution rarely occurs between the two groups in a meta disubstituted compound because this site is too hindered. To make aromatic rings with three adjacent substituents, must therefore be prepared by some other route, such as by starting with substitution of an ortho-disubstituted compound 46 What product would you expect from bromination of p-methylbenzoic acid? the carboxyl group ( -CO2H) is a meta director and the methyl group is an ortho and para director. Both groups direct bromination to the position next to the methyl group 47 Both groups are ortho, para directors, but direct to different positions. Because-NH2 group is a more powerful activator, substitution occurs ortho and para to it. 48 49 50  16.6 Nucleophilic Aromatic Substitution Although aromatic substitution reactions usually occur by an electrophilic mechanism, aryl halides that have electron- withdrawing substituents can also undergo a nucleophilic substitution reaction. Here, the nucleophile OH- substitutes for Cl-. Aryl halides with electron-withdrawing substituents (nitro) ortho and para to the leaving group (Cl) stabilize the anion intermediate through resonance and react with nucleophiles E.W.G 51  Form addition intermediate (Meisenheimer complex) (negatively charged, resonance-stabilized complex) that is stabilized by electron-withdrawal group Halide ion is lost to give aromatic ring Nucleophilic aromatic substitution occurs only if the aromatic ring has an electron-withdrawing substituent in a position ortho or para to the leaving group to stabilize the anion intermediate through resonance 52 53  16.7 Benzyne Halobenzenes without electron-withdrawing substituents don’t react with nucleophiles under most conditions. But at high temperature and pressure even chlorobenzene can be forced to react. Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure The reaction involves an elimination reaction that gives a triple bond The intermediate is called benzyne 54 Mechanism 55 56  16.8 Oxidation of Aromatic Compounds The benzene ring is inert to strong oxidizing agents such as KMnO4 and Na2Cr2O7 Alkyl side chains can be oxidized to CO2H by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring Converts an alkylbenzene into a benzoic acid, ArR ArCO2H 57  The mechanism of side-chain oxidation is complex and involves reaction of C-H bonds at the position next to the aromatic ring to form intermediate benzylic radicals. 58 What aromatic products would you obtain from the KMnO4 oxidation of the following? 59  Bromination of Alkylbenzene Side Chains Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain at the benzylic position. benzoyl peroxide 60  Mechanism of NBS (Radical) Reaction Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical Reacts with Br2 to yield product Br· radical cycles back into reaction to carry chain Br2 produced from reaction of HBr with NBS 61  extra Reaction occurs exclusively at the benzylic position because the benzylic radical intermediate is stabilized by resonance 62  How might you prepare styrene from benzene using reactions you’ve studied? 63 16.9 Reduction of Aromatic Compounds Just as aromatic rings are generally inert to oxidation, they’re also inert to catalytic hydrogenation under conditions that reduce alkene double bonds So can selectively reduce an alkene double bond in the presence of an aromatic ring and carbonyl group Neither the benzene ring nor the ketone carbonyl group is affected. 64  Reduction of an aromatic ring requires more powerful reducing conditions as 1. A platinum catalyst with hydrogen gas at a pressure of several hundred atmospheres (high pressure) 2. Or (a more effective catalyst such as rhodium (Rh)). Under these conditions, aromatic rings are converted into cyclohexanes. 65  Reduction of Aryl Alkyl Ketones In the same way that an aromatic ring activates a neighboring (benzylic) C-H toward oxidation, it also activates a benzylic carbonyl group toward reduction. Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst 66 This two-step sequence of reactions makes it possible to circumvent the carbocation rearrangement problems associated with direct Friedel–Crafts alkylation using a primary alkyl halide 67 How would you prepare diphenylmethane, (Ph)2CH2, from benzene and an acid chloride? 68  16.10 Synthesis Strategies These syntheses require planning and consideration of alternative routes Synthesize 4-bromo-2-nitrotoluene from benzene? 69  The bromination of o-nitrotoluene could be used because the activating methyl group would dominate the deactivating nitro group and direct bromination to the correct position. Unfortunately, a mixture of product isomers would be formed. A Friedel–Crafts reaction can’t be used as the final step because this reaction doesn’t work on a nitro-substituted 70 (strongly deactivated) benzene. The best precursor of the desired product is probably p- bromotoluene Both would also lead unavoidably to a product mixture that would have to be separated. 71 Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene. 72 73 74 75 76 77 78