Substitution by the Elimination-Addition Mechanism

The addition of a nucleophile to an aromatic ring, followed by elimination of a substituent, results in nucleophilic substitution. The major energetic requirement for this 

There are not many successful examples of arylation of carbanions by nucleophilic aromatic substitution. A major limitation is the fact that aromatic nitro compounds often react with carbanions by electron-transfer processes.111 However, such substitution can be carried out under the conditions of the SRN1 reaction (see Section 11.4). 

2-Halopyridines and other re-deficient nitrogen heterocycles are excellent reactants for nucleophilic aromatic substitution.112 Substitution reactions also occur readily for other heterocyclic systems, such as 2-haloquinolines and 1-haloisoquinolines, in which a potential leaving group is adjacent to a pyridine-type nitrogen. 4-Halopyridines and related heterocyclic compounds can also undergo substitution by nucleophilic addition-elimination but are somewhat less reactive. 

Guthrie, in Comprehensive Carbanion Chemistry, Part A, E. Buncel and T. Durst (ed.), Elsevier, Amsterdam, 1980, Chapter 5. 

Mertel, in Heterocyclic Compounds, Vol. 14, Part 2, E. Klingsberg (ed.), Wiley-Interscience, New York, 1961 M. M. Boudakian, in Heterocyclic Compounds, Vol. 14, Part 2, Supplement, R. A. Abramovitch (ed.), Wiley-Interscience, New York, 1974, Chapter 6 B. C. Uff, in Comprehensive Heterocyclic Chemistry, Vol. 2A, A. J. Boulton and A. McKillop (ed.), Pergamon Press, Oxford, 1984, Chapter 2.06. 

The addition of a nucleophile to an aromatic ring, followed by elimination of a substituent, results in nucleophilic substitution. The major energetic requirement for this mechanism is formation of the addition intermediate. The addition step is greatly facilitated by strongly electron-attracting substituents, and nitroaromatics are the best reactants for nucleophilic aromatic substitution. Other EWGs such as cyano, acetyl, and trifluoromethyl also enhance reactivity. 

The pyridine family of heteroaromatic nitrogen compounds is reactive toward nucleophilic substitution at the C(2) and C(4) positions. The nitrogen atom serves to activate the ring toward nucleophilic attack by stabilizing the addition intermediate. This kind of substitution reaction is especially important in the chemistry of pyrimidines. 

The combinations Z = CN, RSOz, COzR, and SR and X = F, Cl, Br, I, ArO, ArS, and (CH3)2NCS2 are among those that have been demonstrated.122 

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Other aryl halides that give stabilized anions can undergo nucleophilic aromatic substitution by the addition-elimination mechanism Two exam pies are hexafluorobenzene and 2 chloropyridme... 

Cycloalkene (Section 5 1) A cyclic hydrocarbon characterized by a double bond between two of the nng carbons Cycloalkyne (Section 9 4) A cyclic hydrocarbon characterized by a tnple bond between two of the nng carbons Cyclohexadienyl anion (Section 23 6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism It is represented by the general structure shown where Y is the nucleophile and X is the leaving group... 

SECTION 10.5. NUCLEOPHILIC AROMAHC SUBSTITUTION BY THE ADDITION-ELIMINATION MECHANISM... 

Nucleophilic Aromatic Substitution by the Addition-Elimination Mechanism... 

Cyclohexadienyl anion (Section 23.6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism. It is represented by the general structure shown, where Y is the nucleophile and X is the leaving group. 

The aryl halide must be one that is reactive toward nucleophilic aromatic substitution by the addition-elimination mechanism. p-Fluoronitrobenzene is far more reactive than fluorobenzene. The reaction shown yields p-nitrophenyl phenyl ether in 92% yield. 

The reason this reaction is suitable is that it involves nucleophilic aromatic substitution by the addition-elimination mechanism on a p-nitro-substituted aryl halide. Indeed, this reaction has been carried out and gives an 80-82% yield. A reasonable synthesis would therefore begin with the preparation of p -ch I oron itrobenzene. 

Acid chlorides react with alcohols to give esters through a nucleophilic acyl substitution by the addition-elimination mechanism discussed on the previous page. Attack... 

First consider the base-catalyzed transesterification of ethyl benzoate with methanol. This is a classic example of nucleophilic acyl substitution by the addition-elimination mechanism. Methoxide ion is sufficiently nucleophilic to attack the ester carbonyl group. Ethoxide ion serves as a leaving group in a strongly exothermic second step. 

Steric hindrance is not nearly as important in electrophilic substitution or in nucleophilic substitution by the addition-elimination mechanism. In both of these reactions, the reagent is attacking the p orbital at right angles to the ring and is some distance from an ortho substituent. 

Large positive p values usually indicate extra electrons in the transition state delocalized into the ring itself. A classic example is nucleophilic aromatic substitution by the addition-elimination mechanism (Chapter 23). The p value is +4.9, but even this large value does not mean a complete anion on the benzene ring as the nitro group, present in all cases, takes most of the negative charge. The substituent X merely helps. 

This equation also describes the overall reaction of either an 5 2 or a nucleophilic aromatic substitution process. In some cases, the only way to distinguish an reaction from these processes is that an is inhibited by radical inhibitors. Another distinguishing feature is that the order of the relative leaving group abilities of halides are opposite that found for nucleophilic aromatic substitution by the addition-elimination mechanism (see Chapter 3). 

The presence of strong electron-withdrawing groups such as NO2 ortho or para to a potential leaving group favors nucleophilic aromatic substitution by the addition-elimination mechanism. Without such groups in these positions, the benzyne mechanism is favored. 

The second reaction is a straightforward substitution by the addition-elimination mechanism activated by the nitro group. The amino group is a spectator. 

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