Addition-elimination mechanism substitution

Mechanism of nucleophilic aromatic substitution by elimination addition (the benzyne mechanism). 

In some, apparently straightforward, displacements, more detailed mechanistic study reveals the operation of alternative mechanisms. For example the reaction of either 3- or 4-bromopyridine with secondary amines in the presence of sodamide/ sodium t-butoxide, produces the same mixture of 3- and 4-dialkylaminopyridines this proceeds via an elimination process (Sn(EA) - Substitution Nucleophilic Elimination Addition) and the intermediacy of 3,4-didehydropyridine (3,4-pyr-idyne)." That no 2-aminated pyridine is produced shows a greater difficulty in generating 2,3-pyridyne, it can however be formed by reaction of 3-bromo-2-chloropyridines with butyllithium" or via the reaction of 3-trimethylsilyl-2-trifluoromethanesulfonyloxypyridine with fluoride." ... 

The benzyne mechanism can be denoted as an Sn(EA) (substitution nucleophilic elimination addition) reaction (reference 7). 

The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution Benzyne... 

THE ELIMINATION-ADDITION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION BENZYNE... 

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... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

Addition-elimination mechanism (Section 23 6) Two stage mechanism for nucleophilic aromatic substitution In the addition stage the nucleophile adds to the carbon that bears... 

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... 

Nucleophilic aromatic substitution (Chapter 23) A reaction m which a nucleophile replaces a leaving group as a sub stituent on an aromatic nng Substitution may proceed by an addition-elimination mechanism or an elimination-addition mechanism... 

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

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

There are several mechanisms by which net nucleophilic aromatic substitution can occur. In this section we will discuss the addition-elimination mechanism and the elimination-addition mechanism. Substitutions via organometallic intermediates and via aryl diazo-nium ions will be considered in Chapter 11 of Part B. 

SECTION 10.6. NUCLEOPHILIC AROMATIC SUBSTITUTION BY THE ELIMINATION-ADDITION MECHANISM... 

FIGURE 23.5 The elimination-addition mechanism of nucleophilic aromatic substitution. 

Although nucleophilic aromatic substitution by the elimination-addition mechanism is most commonly seen with very strong amide bases, it also occurs with bases such as hydroxide ion at high temperatures. A " C-labeling study revealed that hydrolysis of chlorobenzene proceeds by way of a benzyne intennediate. 

Nucleophilic aromatic substitution by the elimination-addition mechanism can lead to substitution on the same carbon that bore the leaving group or on an adjacent carbon. 

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. 

Aryl halides undergo substitution, although not through an Sn2 mechanism, but rather via a two-step addition-elimination mechanism. (An elimination-addition mechanism is also possible see Chapter 13, Problem 12.)... 

The scope of heteroaryne or elimination-addition type of substitution in aromatic azines seems likely to be limited by its requirement for a relatively unactivated leaving group, for an adjacent ionizable substituent or hydrogen atom, and for a very strong base. However, reaction via the heteroaryne mechanism may occur more frequently than is presently appreciated. For example, it has been recently shown that in the reaction of 4-chloropyridine with lithium piperidide, at least a small amount of aryne substitution accompanies direct displacement. The ratio of 4- to 3-substitution was 996 4 and, therefore, there was 0.8% or more pyridyne participation. Heteroarynes are undoubtedly subject to orientation and steric effects which frequently lead to the overwhelming predominance of... 

Halobenzenes undergo nucleophilic aromatic substitution through either of two mechanisms. If the halobenzene has a strongly electron-withdrawing substituent in the ortho or para position, substitution occurs by addition of a nucleophile to the ring, followed by elimination of halide from the intermediate anion. If the halobenzene is not activated by an electron-withdrawing substituent, substitution can occur by elimination of HX to give a benzyne, followed by addition of a nucleophile. 

Primary and secondary aliphatic amines, morpholine and 2-methylaziridine and aniline and even the sterically hindered 2.2,6,6-tetramethylpiperidine readily react with 6-bromo-trithiadiazepine 7, in certain cases in the presence of /V./V-diisopropylethylamine, at room temperature by substitution of the bromine atom ammonia, for example, yields trithiadiazepin-6-amine 22 (R1 = R2 = H). There is compelling evidence that these reactions proceed by an elimination-addition mechanism via the heteroaryne, trithiadiazepyne 21.391... 

The chloro groups of 4,7-dichloro-l,2-diazocines (vide supra) can be sequentially substituted by O-, S- or W-nucleophiles.25 27 The reaction most likely proceeds via an elimination-addition mechanism utilizing the valence tautomeric diazabicyclo[4.2.0]octatriene forms. 

On the other hand, in the case of a-halogenoethyl sulphoxides 503 an SN2-type displacement occurs with mercaptide anions and leads to a-alkylthioethyl sulphoxides 504, while the elimination-addition mechanism is operative with alkoxide anions, affording jS-alkoxyethyl sulphoxides577,596 505 (equation 306). Finally, the reaction of 1-halogeno-l-methylethyl derivatives with both nucleophiles mentioned above occurs via the elimination-addition mechanism596 (equation 307). The substitution reaction can also take place intramolecularly (equation 308) and it proceeds very easily (cf. Section IV.A.2.C)484,600. 

Since chlorine is always in more than a hundred-fold excess compared to bromine the reaction is occurring by pseudo monomolecular kinetics. The reaction occurs via nucleophilic aromatic substitution by an addition-elimination mechanism, the so-called SjsfAr mechanism (ref. 24). 

Mannich bases (see 16-15) of the type RCOCH2CH2NR2 similarly undergo nucleophilic substitution by the elimination-addition mechanism.The nucleophile replaces the NR2 group. 

In the special case of alkaline hydrolysis of N-substituted aryl carbamates, there is another mechanism involving elimination-addition ... 

This mechanism does not apply to unsubstituted or N,N-disubstituted aryl carbamates, which hydrolyze by the normal mechanisms. Carboxylic esters substituted in the a position by an electron-withdrawing group (e.g., CN or COOEt) can also hydrolyze by a similar mechanism involving a ketene intermediate. These elimination-addition mechanisms usually are referred to as ElcB mechanisms, because that is the name given to the elimination portion of the mechanism (p. 1308). 

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