Organic Chemistry William H. Brown & Christopher S. Foote

Aromatics II Chapter 20 Chapter 21

Reactions of Benzene  The most characteristic reaction of aromatic compounds is substitution at a ring carbon

Reactions of Benzene

Electrophilic Aromatic Sub  Electrophilic aromatic substitution:  Electrophilic aromatic substitution: a reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile  We study several common types of electrophiles how each is generated the mechanism by which each replaces hydrogen

Chlorination Step 1: formation of a chloronium ion

Chlorination Step 2: attack of the chloronium ion on the aromatic ring Step 3: proton transfer regenerates the aromatic character of the ring

EAS: General Mechanism  A general mechanism  General question: what is the electrophile and how is it generated?

Nitration  The electrophile is NO 2 +, generated in this way

Nitration Step 1: attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile) Step 2: proton transfer regenerates the aromatic ring

Nitration  A particular value of nitration is that the nitro group can be reduced to a 1° amino group

Sulfonation  Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide

Friedel-Crafts Alkylation  Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group

Friedel-Crafts Alkylation Step 1: formation of an alkyl cation as an ion pair Step 2: attack of the alkyl cation on the aromatic ring Step 3: proton transfer regenerates the aromatic ring

Friedel-Crafts Alkylation  There are two major limitations on Friedel-Crafts alkylations 1. carbocation rearrangements are common

Friedel-Crafts Alkylation the isobutyl chloride/AlCl 3 complex rearranges to the tert-butyl cation/AlCl 4 - ion pair, which is the electrophile

Friedel-Crafts Alkylation 2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron-withdrawing groups

Friedel-Crafts Acylation  Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group

Friedel-Crafts Acylation  The electrophile is an acylium ion

Friedel-Crafts Acylation an acylium ion is a resonance hybrid of two major contributing structures  F-C acylations are free of a major limitation of F-C alkylations; acylium ions do not rearrange

Friedel-Crafts Acylation  A special value of F-C acylations is preparation of unrearranged alkylbenzenes

Other Aromatic Alkylations  Carbocations are generated by treatment of an alkene with a protic acid, most commonly H 2 SO 4, H 3 PO 4, or HF/BF 3

Other Aromatic Alkylations by treating an alkene with a Lewis acid and by treating an alcohol with H 2 SO 4 or H 3 PO 4

Di- and Polysubstitution orientationrate  Existing groups on a benzene ring influence further substitution in both orientation and rate  Orientation: certain substituents direct preferentially to ortho & para positions; others direct preferentially to meta positions substituents are classified as either ortho-para directingmeta directing ortho-para directing or meta directing

Di- and Polysubstitution  Rate certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower activatingdeactivatingsubstituents are classified as activating or deactivating toward further substitution

Di- and Polysubstitution -OCH 3 is ortho-para directing

Di- and Polysubstitution -NO 2 is meta directing

Di- and Polysubstitution

 From the information in Table 21.1, we can make these generalizations alkyl, phenyl, and all other groups in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other groups are meta directing all ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating

Di- and Polysubstitution the order of steps is important

Theory of Directing Effects  The rate of EAS is limited by the slowest step in the reaction  For almost every EAS, the rate-determining step is attack of E + on the aromatic ring to give a resonance-stabilized cation intermediate  The more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction

Theory of Directing Effects  For ortho-para directors, ortho-para attack forms a more stable cation than meta attack ortho-para products are formed faster than meta products  For meta directors, meta attack forms a more stable cation than ortho-para attack meta products are formed faster than ortho-para products

Theory of Directing Effects -OCH 3 ; assume meta attack

Theory of Directing Effects -OCH 3 : assume ortho-para attack

Theory of Directing Effects -NO 2 ; assume meta attack

Theory of Directing Effects -NO 2 : assume ortho-para attack

Activating-Deactivating  Any resonance effect  Any resonance effect, such as that of -NH 2, -OH, and -OR, that delocalizes the positive charge on the cation intermediate lowers the activation energy for its formation, and has an activating effect toward further EAS  Any resonance or inductive effect  Any resonance or inductive effect, such as that of -NO 2, -CN, -CO, or -SO 3 H, that decreases electron density on the ring deactivates the ring toward further EAS

Activating-Deactivating  Any inductive effect  Any inductive effect, such as that of -CH 3 or other alkyl group, that releases electron density toward the ring activates the ring toward further EAS  Any inductive effect  Any inductive effect, such as that of -halogen, - NR 3 +, -CCl 3, or -CF 3, that decreases electron density on the ring deactivates the ring toward further EAS

Halogens for the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger the net effect is that halogens are deactivating but ortho-para directing

Nucleophilic Aromatic Sub.  Aryl halides do not undergo nucleophilic substitution by either S N 1 or S N 2 pathways  They do undergo nucleophilic substitutions, but by mechanisms quite different from those of nucleophilic aliphatic substitution  Nucleophilic aromatic substitutions are far less common than electrophilic aromatic substitutions

Benzyne Intermediates  When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide. Neutralization with HCl gives phenol.

Benzyne Intermediates the same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol the same type of reaction can be brought about using of sodium amide in liquid ammonia

Benzyne Intermediates  -elimination of HX gives a benzyne intermediate, that then adds the nucleophile to give products

Nu Addition-Elimination when an aryl halide contains electron-withdrawing NO 2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily neutralization with HCl gives the phenol

Meisenheimer Complex reaction involves a Meisenheimer complex intermediate

Prob 21.7 Write a mechanism for each reaction.

Prob 21.8 Offer an explanation for the preferential nitration of pyridine in the 3 position rather than the 2 position.

Prob 21.9 Offer an explanation for the preferential nitration of pyrrole in the 2 position rather than in the 3 position.

Prob Predict the major product(s) from treatment of each compound with HNO 3 /H 2 SO 4.

Prob Account for the fact that N-phenylacetamide is less reactive toward electrophilic aromatic substitution than aniline.

Prob Propose an explanation for the fact that the trifluoromethyl group is meta directing.

Prob Arrange the compounds in each set in order of decreasing reactivity toward electrophilic aromatic substitution.

Prob (cont’d) Arrange the compounds in each set in order of decreasing reactivity toward electrophilic aromatic substitution.

Prob Draw a structural formula for the major product of nitration of each compound.

Prob Which ring in each compound undergoes electrophilic aromatic substitution more readily? Draw the product of nitration of each compound.

Prob Propose a mechanism for the formation of bisphenol A.

Prob Propose a mechanism for the formation of BHT.

Prob Propose a mechanism for the formation of DDT.

Prob Propose a mechanism for this reaction.

Prob Account for the regioselectivity of the nitration in Step 1, and propose a mechanism for Step 2.

Prob Propose a mechanism for the displacement of chlorine by (1) the NH 2 group of the dye and (2) an -OH group of cotton.

Prob Show how to prepare (a) and (b) from 1-phenyl-1- propanone.

Prob Show how to bring about each conversion.

Prob Propose a synthesis for each compound from benzene.

Prob Propose a synthesis of 2,4-D from chloroacetic acid and phenol.

Prob Propose a synthesis of this compound from benzene.

Prob Propose a synthesis of this compound from 3- methylphenol.

Prob Propose a synthesis of this compound from toluene and phenol.

Prob Propose a mechanism for this example of chloromethylation (introduction of a CH 2 Cl group on an aromatic ring). Show how to convert the product of chloromethylation to piperonal.

Prob Given this retrosynthetic analysis, propose a synthesis for Dinocap from phenol and 1-octene.

Prob Show how to synthesize this trichloro derivative of toluene from toluene.

Prob Given this retrosynthetic analysis, propose a synthesis for bupropion.

Aromatics II End Chapter 21