Electophilic Aromatic Substituion

Electophilic Aromatic Substituion

16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurrys 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 replaces a proton on benzene with another electrophile McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 2 16.1 Bromination of Aromatic Rings Benzenes 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 FeBr3 is added as a catalyst to polarize the bromine reagent McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 3 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 and therefore high in energy (see Figure 16.2) McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 4 Formation of Product from Intermediate The cationic addition

intermediate transfers a proton to FeBr4- (from Brand FeBr3) This restores aromaticity (in contrast with addition in alkenes) McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 5 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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003

6 Aromatic Chlorination and Iodination Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution with the addition of other reagents to promote the reaction Chlorination requires FeCl3 Iodine must be oxidized to form a more powerful I + species (with Cu+ or peroxide) McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003

7 Aromatic Nitration The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion) The reaction with benzene produces nitrobenzene McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 8

Aromatic Sulfonation Substitution of H by SO3 (sulfonation) Reaction with a mixture of sulfuric acid and SO3 Reactive species is sulfur trioxide or its conjugate acid Reaction occurs via Wheland intermediate and is reversible McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 9

Alkali Fusion of Aromatic Sulfonic Acids Sulfonic acids are useful as intermediates Heating with NaOH at 300 C followed by neutralization with acid replaces the SO3H group with an OH Example is the synthesis of p-cresol McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 10

16.3 Alkylation of Aromatic Rings: The FriedelCrafts Reaction Aromatic substitution of a R+ for H Aluminum chloride promotes the formation of the carbocation Wheland intermediate forms McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003

11 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) Will not work with rings containing an amino group substituent or a strongly electron-withdrawing group McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003

12 Control Problems Multiple alkylations can occur because the first alkylation is activating McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 13 Carbocation Rearrangements During

Alkylation Similar to those that occur during electrophilic additions to alkenes Can involve H or alkyl shifts McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 14 16.4 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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 15 Mechanism of Friedel-Crafts Acylation Similar to alkylation Reactive electrophile: resonance-stabilized acyl

cation An acyl cation does not rearrange McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 16 16.5 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 paradirecting deactivators, and meta-directing deactivators McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 17 Origins of Substituent Effects An interplay of inductive effects and resonance effects Inductive effect - withdrawal or donation of electrons through a bond

Resonance effect - withdrawal or donation of electrons through a bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 18 Inductive Effects Controlled by electronegativity and the polarity of bonds in functional groups

Halogens, C=O, CN, and NO2 withdraw electrons through bond connected to ring Alkyl groups donate electrons McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 19 Resonance Effects Electron Withdrawal C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance

electrons flow from the rings to the substituents McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 20 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

McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 21 Contrasting Effects Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring Resonance interactions are generally weaker, affecting orientation The strongest effects dominate

McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 22 16.6 An Explanation of Substituent Effects Activating groups donate electrons to the ring, stabilizing the Wheland intermediate

(carbocation) Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 23 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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 24 Ortho- and Para-Directing Activators: OH and NH2 Alkoxyl, and amino groups have a strong, electron-

donating resonance effect Most pronounced at the ortho and para positions McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 25 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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 26 Meta-Directing Deactivators Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by deactivation from carbocation intermediate Resonance cannot produce stabilization

McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 27 Summary Table: Effect of Substituents in Aromatic Substitution McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 28

16.7 Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 29 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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 30 Meta-Disubstituted Compounds Are Unreactive The reaction site is too hindered To make aromatic rings with three adjacent

substituents, it is best to start with an orthodisubstituted compound McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 31 16.8 Nucleophilic Aromatic Substitution Aryl halides with electron-withdrawing substituents ortho and para react with

nucleophiles Form addition intermediate (Meisenheimer complex) that is stabilized by electronwithdrawal Halide ion is lost to give aromatic ring McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 32 16.9 Benzyne

Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340C under high pressure The reaction involves an elimination reaction that gives a triple bond The intermediate is called benzyne McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 33 Evidence for Benzyne as an

Intermediate Bromobenzene with C only at C1 gives substitution product with label scrambled between C1 and C2 Reaction proceeds through a symmetrical intermediate in which C1 and C2 are equivalent must be benzyne 14 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 34

Structure of Benzyne Benzyne is a highly distorted alkyne The triple bond uses sp2-hybridized carbons, not the usual sp The triple bond has one bond formed by pp overlap and by weak sp2sp2 overlap McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 35

16.10 Oxidation of Aromatic Compounds 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, ArR ArCO2H McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 36

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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 37 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 McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 38 16.11 Reduction of Aromatic Compounds

Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the presence of an aromatic ring Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium catalysts) McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 39

Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group toward reduction Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 40 16.12 Synthesis Strategies These syntheses require planning and consideration

of alternative routes Work through the practice problems in this section following the general guidelines for synthesis (and retrosynthetic analysis in 8.10) McMurry Organic Chemistry 6th edition Chapter 1 6 (c) 2003 41

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