Nucleophilic substitution process elimination/addition reactions

Two other important modes of substitution require mention here. They are the SNAr and elimination-addition reactions. Actually, it is sometimes difficult to distinguish between true aromatic nucleophilic substitutions and addition-elimination processes. The second group involves pyridyne intermediates (Scheme 53). Both of these reaction types are discussed fully under substituent reactions (Chapter 2.06). 

Chapters 7-10 have introduced three basic kinds of organic reactions nucleophilic substitution, P elimination, and addition. In the process, many specific reagents have been discussed and the stereochemistry that results from many different mechanisms has been examined. How can we keep track of all the reactions ... 

Among the most common reaction types encountered in biochemical processes are the following (1) nucleophilic substitution, (2) elimination, (3) addition, (4) isomerization, and (5) oxidation-reduction. Each will be briefly described. 

The amination of 2.4-diphenyl-1,3,5-triazine (7, X = H) with potassium amide in anhydrous liquid ammonia at -33°C occurs by a Chichibabin-type reaction, i.e. replacement of H" by NH via nucleophilic substitution involving an addition-elimination process (SsAE). In contrast, the 2-methylsulfanyl derivative 7 (X = SMe) is aminated nearly exclusively by a ringopening-ring-closing sequence [Sn(ANRORC)].52... 

Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition step is generally the rate-limiting one. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process. 

Nucleophilic substitutions are in many cases facile processes in heterocyclic chemistry. Also, in the area of the present chapter, many such routine transformations have been carried out. Such transformations are summarized in Table 6, where the structures of the starting compounds, products, the reagents, yields, and references are listed. These include reactions of halogen, methoxy, and methylsulfanyl derivatives with amines or alkoxides. One exceptional case (Table 6, entry 9) should be pointed out this exchange reaction, unlike the others in this table, proceeds via an elimination-addition mechanism. A few related transformations that follow more complicated pathways and therefore could not be classified unambiguously into this table, can be found in Table 7 in Section 11.17.5.6.5. 

A reaction in which one functional group (see p.lO) is replaced by another is termed substitution. Depending on the process involved, a distinction is made between nucleophilic and electrophilic substitution reactions (see chemistry textbooks). Nucleophilic substitutions start with the addition of one molecule to another, followed by elimination of the so-called leaving group. 

A mechanism for heteroaromatic nucleophilic substitution which is under considerable active study at the present time is the SRN process, which often competes with the addition-elimination pathway. Srn reactions are radical chain processes, and are usually photochemi-cally promoted. An example is shown in Scheme 22, where (60) is formed by the SrnI pathway and (61) via an initial addition reaction (82JOC1036). 

Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions, which compete with the desired DoM process. 

Typical phase transfer catalysis in liquid-liquid systems combines processes in which Na+ or K+ salts of inorganic and organic anions derived from strong adds (phenolates, thiolates, carboxylates, etc.) are continuously transferred from aqueous (often alkaline) solutions to the organic phase by the phase transfer catalysts. Applications include nucleophilic substitution, addition, elimination, oxidation, and reduction reactions. 

Unactivated aryl halides also undergo nucleophilic displacement via electron transfer in the initial step the so-called SRN1 mechanism. It is now clear that in the case of heteroaromatic compounds, nucleophilic substitution by the Srn process often competes with the addition-elimination pathway. The SRN reactions are radical chain processes, and are usually photochemically promoted. For example, ketone (895) is formed by the SRN1 pathway from 2-chloroquinoxaline (894) (82JOC1036). 

Intramolecular nucleophilic substitution by the anions of o-haloanilides is another viable oxindole synthesis. This is a special example of the category Ic process described in Section 3.06.2.3. The reaction is photo-stimulated and the mechanism is believed to be of the electron-transfer type SRN1 rather than a classical addition-elimination mechanism. The reaction is effective when R = H if 2 equivalents of the base are used to generate the dianion (equation 202) (80JA3646). 

Reactions of alkynyliodonium salts 119 with nucleophiles proceed via an addition-elimination mechanism involving alkylidenecarbenes 120 as key intermediates. Depending on the structure of the alkynyliodonium salt, specific reaction conditions, and the nucleophile employed, this process can lead to a substituted alkyne 121 due to the carbene rearrangement, or to a cyclic product 122 via intramolecular 1,5-carbene insertion (Scheme 50). Both of these reaction pathways have been widely utilized as a synthetic tool for the formation of new C-C bonds. In addition, the transition metal mediated cross-coupling reactions of alkynyliodonium salts are increasingly used in organic synthesis. 

Isolation and study of the behaviour of the intermediate. Although a substituted acetylene is the intermediate in the elimination-addition route, its isolation is dependent on the relative rates of its formation and destruction by the nucleophilic addition. Acetylenes can sometimes be isolated as the main reaction products, but in other cases, they have only been detected spectroscopically, or they may be trapped if they are very reactive. Detection of acetylene does not always prove that it is a reaction intermediate. Since generalization regarding the stereochemistry of the nucleophilic addition to acetylenes may be misleading, the independent behaviour (stereochemistry of addition, rate of disappearance) of the alleged intermediate acetylene should be studied. In favourable cases, these data enable quantitative dissection of the substitution process into its addition-elimination and elimination-addition components. 

In the addition-elimination routes, either via a carbanionic intermediate (I) or via a neutral adduct (II), the anionic nucleophile Nu or the neutral nucleophile NuH attacks the /3-carbon with the expulsion of X. In the a,/8-route (IV), the /9,/3-route (VI) and the /8, y- elimination-addition routes (VII), HX is eliminated in the initial step, and the nucleophile and hydrogen are then added to the intermediates. Substitution occurs also by heterolytic C—X bond cleavage in an SN1 process (X). Initial prototropy followed by substitution can also give vinylic substitution products (XII, XIV), as well as two consecutive Sn2 reactions (XV) where the leaving group leaves from an allylic position. 

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