1 Substitution Reactions of Benzene and Its Derivatives: Electrophilic Addition/Elimination Reactions. 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

2 Aromatic Substitutions via the Wheland Intermediates All electrophile additions involve a cationic intermediate that was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate.

3 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 FeBr 3 is added as a catalyst to polarize the bromine reagent

4 Addition Intermediate in Bromination The addition of bromine occurs in two steps In the first step the  electrons act as a nucleophile toward Br 2 (in a complex with FeBr 3 ) This forms a cationic addition intermediate from benzene and a bromine cation The intermediate is not aromatic and therefore high in energy

5 Formation of the Product from the Intermediate The cationic addition intermediate transfers a proton to FeBr 4 - (from Br - and FeBr 3 ) This restores aromaticity (in contrast with addition in alkenes)

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 FeCl 3 Iodine must be oxidized to form a more powerful I + species (with Cu + or peroxide)

7 Aromatic Nitration and Sulfonation

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9 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Aromatic substitution of a R + for H Aluminum chloride promotes the formation of the carbocation 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)

10 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction

11 Multiple alkylations can occur because the first alkylation is activating

12 Carbocation Rearrangements During Alkylation

13 Carbocation Rearrangements During Alkylation

14 Acylation of Aromatic Rings Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl 3 introduces acyl group,  COR

15 Mechanism of Friedel-Crafts Acylation

16 Reduction of Aryl Alkyl Ketones Allows Synthesis of Non-rearranged Alkyl Benzenes. Aromatic ring activates neighboring carbonyl group toward reduction. Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst, or Wolff-Kishner or Clemensen reductions.

17 Reduction of Aryl Alkyl Ketones Allows Synthesis of Non-rearranged Alkyl Benzenes.

18 Summary of reduction nucleophiles in 1,2-additions to aromatic C=O groups.

19 Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or (much) less reactive than benzene and affect the orientation of the reaction. There substituents are: ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators.

20 Summary Table: Effect of Substituents in Aromatic Substitution

21 The 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.

22 Origins of Substituent Effects: Inductive Effects The overall effect of a substituent is defined by the interplay of inductive effects and resonance effects. Inductive effect - withdrawal or donation of electrons through  bonds. Controlled by electronegativity and the polarity of bonds in functional groups, i.e. halogens, C=O, CN, and NO 2 withdraw electrons through  bond connected to ring. Alkyl group inductive effect is to donate electrons.

23 Origins of Substituent Effects: Resonance Effects 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. C=O, CN, and NO 2 substituents withdraw electrons from the aromatic ring by resonance, i.e. the  electrons flow from the rings to the substituents.

24 Origins of Substituent Effects: Resonance Effects 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. Halogen, OH, alkoxyl (OR), and amino substituents donate electrons, i.e. the  electrons flow from the substituents to the ring.

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26 Ortho- and Para-Directing Activators: Alkyl Groups

27 Ortho- and Para-Directing Activators: OH and NH 2

28 Ortho- and Para-Directing Deactivators: Halogens

29 Meta-Directing Deactivators Inductive and resonance effects reinforce each other. Ortho and para intermediates destabilized by deactivation of the carbocation intermediate

30 Disubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the same, the result is additive.

31 Disubstituted Benzenes: Opposition of Effects If the directing effects of the two groups are different, the more powerful activating group decides the principal outcome. Usually the mixture of products results.

32 Linked Benzenes: Opposition of Effects

33 Diazonium Salts: The Sandmeyer Reaction Primary arylamines react with HNO 2, yielding stable arenediazonium salts. The N 2 group can be replaced by a nucleophile.

34 Reactions of Arenediazonium Salts Allow Formation of “Impossibly” Substituted Aromatic Rings. Typical synthetid sequence consists of: (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic substitution

35 Preparation of Aryl Halides Reaction of an arenediazonium salt with CuCl or CuBr gives aryl halides (Sandmeyer Reaction). Aryl iodides form from reaction with NaI without a copper(I) salt.

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37 Preparation of Aryl Nitriles and Carboxylic Acids An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be hydrolyzed to ArCOOH.

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39 Reduction to a CH aromatic bond By treatment of a diazonium salt with hypophosphorous acid, H 3 PO 2

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