2.6-Di-tert-buty/-4-methylphenol.alternatively known as butylatedhydroxytoluene or BHT (seeProblem 22.23) is often used asan antioxidant to retard spoilage.Inset: a model of BHT.

OUTLINE22.1 Electrophilic Aromatic

Substitution22.2 Disubstitution and

Polysubstitution22.3 Nucleophilic Aromatic

Substitution

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840

By far the most characteristic reaction of aromatic compounds is substi-tution at a ring carbon. In this reaction, one of the ring hydrogens isreplaced by another atom or group of atoms. Some groups that can beintroduced directly on the ring are the halogens, the nitro (-N02) group, thesulfonic acid (-S03H) group, alkyl (-R) groups, and acyl (RCO-) groups.Each of these substitution reactions is represented in the following equations.

Halogenation:

< )-H + Cl2 FeCl3 l < )-CI + HCIChlorobenzene

Nitration:

.. ,,

,..,

,.

Cation Intermediate

Step 2: Attack of the chloronium ion (a strong electrophile) on the 7T system(a weak nucleophile) of the aromatic ring gives a resonance-stabilized cationintermediate, here represented as a hybrid of three contributing structures.Notice that the positive charge is located primarily at the ortho and para posi-tions of the resonance-stabilized cation intermediate. This distribution of posi-tive charge is clearly visible in the electrostatic potential surface of the cationintermediate, as the dark blue color at the ortho and para positions.

slow, ratedetermining

rvH'-------J\(;"l:

+

Step 3: Proton transfer from the cation intermediate to FeC14- forms HCl,regenerates the Lewis acid catalyst, and gives chlorobenzene.

Cation intermediate Chlorobenzene

Treating benzene with bromine in the presence of ferric chloride or alumi-num chloride gives bromobenzene and HBr. The mechanism of this reaction isthe same as that for the chlorination of benzene.

We can write the following general two-step mechanism for electrophilic aromaticsubstitution. The first and rate-determining step is attack of the strong electrophile,E+, by the weakly nucleophilic 7T electrons of the aromatic ring to give a resonance-stabilized cation intermediate. The second and faster step, loss of H+ from the cationintermediate, regenerates aromaticity in the ring and gives the product

Step 1:slow, rate

detennining ) < ~:Step 2:

Electrophile

0 + H fast 0-'1_ E ------+ ~ # E + H+Resonance-stabilizedcation intermediate

The major difference between addition of halogen to an alkene and halogensubstitution on an aromatic ring centers on the fate of the cationic intermedi-ate formed in the first step of each reaction. Recall from Section 6.3D that addi-tion of chlorine or bromine to an alkene is a two-step process, the first and slowerstep of which is formation of a bridged halonium ion intermediate. This cationicintermediate then reacts with chloride or bromide ion to complete the addition.With aromatic compounds, the cationic intermediate instead loses H+ to regener-ate the aromatic ring and regain the large resonance stabilization. No such reso-nance stabilization is regained in the case of an alkene. The energy diagram inFigure 22.1 shows both addition and substitution reactions of benzene. Additioncauses loss of the aromatic resonance energy and is disfavored except underextreme circumstances.

842 Chapter 22 Reactions of Benzene and Its Derivatives

Step 2: Redistribution of electrons of the carbon-chlorine bond gives an ion paircontaining an acylium. ion.Acylium ion

A resonance-lltabilized cationwith the structure [RC=O]+or [ArC=O]+. The positivecharge is delocalized over boththe carbonyl carbon and thecarbonyl oxygen.

:0: CI11 .. -1

R-C-CI: r + ""Al-CII

CI

:0: CIII + 1-

R-C-CI-Al-CI'-:;' I

CI

An acyl chloride(a Lewis base)

Aluminumchloride

(a Lewis acid)

A molecular complex witha positive charge on

chlorine and a negativecharge on aluminum

An ion paircontaining an

acylium ion

Of the two major contributing structures that can be drawn for an acyliumion, the one with complete valence shells for both carbon and oxygen makesthe greater contribution to the hybrid.

+R-C=O:

'V.

Both atoms have

A benzyne intermediateCartoon orbital

o7T bonding, but ofreduced strengthbecause of poororbital overlap

Step 3: Proton transfer from ammonia to the carbanion intermediate gives oneof the observed substitution products and generates a new amide ion.

The bonding in a benzyne intermediate, and also the reason for its extremelyreactive nature, can be pictured in the following way. According to molecularorbital theory, the benzene ring retains its planarity, 7T bonding, and aromaticcharacter. The adjacent sp2 orbitals formerly bonding to a halogen and a hydrogennow overlap to form the second 7T bond of the benzyne triple bond. The problemis that the atomic orbitals forming this 7T bond are not parallel as in acetylene andunstrained alkynes but, rather, lie at an angle of 1200 to the bond axis connect-ing them. Consequently, the overlap between these orbitals is reduced. Reducedoverlap, in turn, means a weaker and more reactive 7T bond. Therefore, the second7T bond of the benzyne intermediate undergoes addition very readily to form twonew and stronger (T bonds. The relatively high energy of the benzyne intermediateis presumably why such high temperatures are required for these reactions.

B. Nucleophilic Substitution by Addition-EliminationAromatic halides are normally quite inert to the types of nucleophiles that read-ily displace halide ions from alkyl halides. However, when an aromatic compoundcontains strong electron-withdrawing nitro groups ortho or para (or both) to thehalogen, nucleophilic aromatic substitution occurs quite readily. For example,when 1-chloro-2,4-dinitrobenzene is heated at reflux in aqueous sodium carbonatefollowed by treatment with aqueous acid, it is converted in nearly quantitative yieldto 2,4-dinitrophenol.

N"l!C03,H20)100C

l-Chloro-2,4-dinitrobenzene

Sodium 2,4-dinitro-phenoxide

2,4-Dinitrophenol

One application of this reaction is the synthesis of 2,4-dinitrophenylhydrazine,a reagent that was once commonly used to prepare derivatives of aldehydes andketones (Section 16.8B).

+ Hel

PROBLEMS

2-Nitropyrrole

3-Nitropyridine

Pyrrole

O a N02I / + HN03 _H--=2_S2.4~. I + H 0.'/ 3000C.& 2N NPyridine

Under these acidic conditions, the species undergoing nitration is not pyridine but itsconjugate acid. Write resonance contributing structures for the intermediate formedby attack of N02+ at the 2, 3, and 4 positions of the conjugate acid of pyridine. Fromexamination of these intermediates, offer an explanation for preferential nitration atthe 3 position.

22.9 Pyrrole undergoes electrophilic aromatic substitution preferentially at the 2 posi-tion as illustrated by the synthesis of 2-nitropyrrole.

Write resonance contributing structures for the intermediate formed by attack ofN02+ at the 2 and 3 positions of pyrrole. From examination of these intermediates,offer an explanation for preferential nitration at the 2 position.

22.10 Addition of m-xylene to the strongly acidic solvent HF/SbF5 at -45C gives a new spe-cies, which shows IH-NMR resonances at 82.88 (3H), 3.00 (3H), 4.67 (2H), 7.93 (lH),7.83 (lH), and 8.68 (lH). Assign a structure to the species giving this spectrum.

O~ + HN03 CH3COOH t:A~ 0--"5-oC--' 0 + H 2N N 2I IH H

00"

Morphine, a potent painkillerisolated from the ripe seed headsof the opium poppy, has been alead drug for chemists in search ofpotent but less addicting syntheticpainkillers. See Problem 23.21.Insert: a model of morphine.

OUTLINE23.1 Structure and

Classification23.2 Nomenclature23.3 Chirality of Amines and

Quaternary AmmoniumIons

23.4 Physical Properties23.5 Basicity23.6 Reactions with Acids23.7 Preparation23.8 Reaction with Nitrous

Acid23.9 Hofmann Elimination23.10 Cope Elimination

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Carbon, hydrogen, and oxygen are the three most common elements inorganic compounds. Because of the wide distribution of amines in the bio-logical world, nitrogen is the fourth most common element in organic com-pounds. The most important chemical properties of amines are their basicity andtheir nucleophilicity.

23.1 Structure and ClassificationAmines are derivatives of ammonia in which one or more hydrogens are replaced byalkyl or aryl groups. Amines are classified as primary, secondary, or tertiary, depend-ing on the number of carbon atoms bonded directly to nitrogen (Section 1.3B).

CH3ICH3-~:

CH3Methylamine(a 1 amine)

Dimethylamine(a 2 amine)

Trimethylamine(a 3 amine)

Aliphatic amineAn amine in which nitrogen isbonded only to alkyl groups.

Aromatic amineAn amine in which nitrogenis bonded to one or more arylgroups.

Amines are further divided into aliphatic and aromatic amines. In an aliphaticamine, all carbons bonded to nitrogen are derived from alkyl groups; in an aro-matic amine, one or more of the groups bonded to nitrogen are aryl groups.

880

Aniline(a }O aromatic amine)

N-Methylaniline(a 2 aromatic amine)

Benzyldimethylamine(a 3 aliphatic amine)