Addition-elimination process for

Figure 8-29. The addition-elimination process for the displacement of halide ion from a 4-halo-pyridine. The same mechanism is operative for 2-halopyridines. The key feature is stabilisation of the charge on the electronegative nitrogen atom in the intermediate.

As with other aromatic substitutions, the substitution step itself can be considered to involve an approximately sps hybridization at the carbon atom under attack (10). In the idealized substitution process shown in Eq. (16), 10 may constitute either an intermediate or a transition state. If proton loss ensues directly, the process is properly called a substitution. In other situations the intermediate 10 may become allied with a radical or an anion, leading thereby to a covalent adduct 11. The final substituted product 12 may then be formed either by the elimination of H—Z (first H, then Z) or by the reversal to 10, followed by proton loss. The first case is a classical example of an addition-elimination halogenation, where the adduct is an essential species in the process. In the second case, structure 10 is a common intermediate for both the substitution and the addition reactions. Being merely a diversion of 10, the addition product is not essential to the substitution. In consequence of this, the isolation of adduct 11 may not mean that addition-elimination is the principal pathway of substitution reversal to 10 may be faster than the elimination of H—Z ( 2, k3>ki). On the other hand, the mere failure to detect adduct 11 does not rule out an addition-elimination process, for dehydrohalogenation of adduct 11 may be much faster than its formation (ki>klt k2). 

The reaction of the subhalides with haloethylenes apparently proceeds via a stepwise addition-elimination process. For a vinyl halide, this may be summarized as follows ... 

Scheme 2. Addition-elimination process for aromatic halogen exchange.

The synthesis of aziridines through reactions between nitrenes or nitrenoids and alkenes involves the simultaneous (though often asynchronous vide supra) formation of two new C-N bonds. The most obvious other alternative synthetic analysis would be simultaneous formation of one C-N bond and one C-C bond (Scheme 4.26). Thus, reactions between carbenes or carbene equivalents and imines comprise an increasingly useful method for aziridination. In addition to carbenes and carbenoids, ylides have also been used to effect aziridinations of imines in all classes of this reaction type the mechanism frequently involves a stepwise, addition-elimination process, rather than a synchronous bond-forming event. 

Starnes et al.hl have also suggested that the head adduct may undergo p-scission to eliminate a chlorine atom which in turn adds VC to initiate a new polymer chain. Kinetic data suggest that the chlorine atom does not have discrete existence. This addition-elimination process is proposed to he the principal mechanism for transfer to monomer during VC polymerization and it accounts for the reaction being much more important than in other polymerizations. The reaction gives rise to terminal chloroallyl and 1,2-dichlorocthyl groups as shown in Scheme 4.8. 

An alternative to the above mechanism is that acetoxylation is an addition-elimination process involving N02 and OAc , leading to nitro and acetoxy products77, and it follows that this process would be less likely to occur, for example, with mesitylene and significantly perhaps, experiments seeking acetoxylation in mesitylene have failed78 on the other hand, mesitylene is a very reactive substrate so it could be that an alternative nitrating species is involved here. 

A chiral sulfoxide can be used as a leaving group for the asymmetric induction via addition-elimination process. 6-Lactam enolates are converted into the corresponding nitroalkenes substituted with lactams (Eq. 4.101).127... 

For example, in the instance of 9-chloroacridine, the attachment of the halogen (leaving group) at a suitably electrophilic carbon site allows the occurrence of a replacement reaction, presumably occurring via an addition-elimination procedure for phosphorus attachment, followed by the common nucleophilic displacement (ester cleavage) of the Michaelis-Arbuzov process (Figure 6.1).4... 

The use of transition metals for the facilitation of substitution reactions on vinylic carbon has proven to be quite successful. For example, vinylic chlorides in the presence of nickel(II) chloride react with trialkyl phosphites to substitute phosphorus for the halide (Figure 6.17j.71-72 While reminiscent of a direct Michaelis-Arbuzov reaction, including final dealkylation by a chloride ion, the reaction actually involves an addition-elimination process. It appears that chloride provides a more facile reaction than bromide, a characteristic noted in several reaction systems. 

Pyrimidinyl halides are not only precursors for Pd-catalyzed reactions, but also important pharmaceuticals in their own right. One of the most frequently employed approaches for halopyrimidine synthesis is direct halogenation. When pyrimidinium hydrochloride and 2-aminopyrimidine were treated with bromine, 5-bromopyrimidine and 2-amino-5-bromopyrimidine were obtained, respectively, via an addition-elimination process instead of an aromatic electrophilic substitution [4, 5], Analogously, 2-chloro-5-bromopyrimidine (1) was generated from direct halogenation of 2-hydroxypyrimidine [6], Treating 1 with HI then gave to 2-iodo-5-bromopyrimidine (2). In the preparation of 5-bromo-4,6-dimethoxypyrimidine (4), N-bromosuccinimide was found to be superior to bromine for the bromination of 4,6-dimethoxypyrimidine (3) [7]. 

Fluorouracil has been used for some time for cancer treatment. Its preparation using fluorine is operated commercially (RC.R. Inc) and has been the focus of numerous studies [12, 150] in the past. In a more recent study, the products obtained upon fluorination of uracil, usually carried out in acetic acid solvent, indicate that the reactions proceed via an addition-elimination process involving radical cation intermediates (Fig. 63) [156]. 

Starting with 2,4-diphenyl-1,3,5-triazine and KNH2-NH3, adduct 63 (Table XIII) is formed.116 The reaction mixture slowly leads to 2-amino-4,6-diphenyI-l,3,5-triazine by a mechanism that is shown by l5N labeling to consist of an addition-elimination process. Therefore, adduct 63 is likely to be a true reaction intermediate for the Chichibabin reaction. Although a related substrate, 2-methyIthio-4,6-diphenyl-1,3,5-triazine, gives the 2-amino derivative exclusively by the ANRORC mechanism, which is likely to involve the addition of NH2" to a phenyl-bearing position in the initial step, the formation of such adducts as 64 has not been reported.116... 

Comparison of kh with the calculated k,ot = 0.15 d 1 shows that abiotic hydrolysis is the most important removal mechanism for BzC in the pond ( 75%>) thus, you have to worry about the transformation product benzyl alcohol (Fig. 12.1). About 7% is removed by flushing (kw = VIQ = 0.01 d"1), and the rest by other processes. Considering the properties of benzyl chloride (e.g., Kj0Vi, Ajaw, see Appendix C), the most likely additional elimination processes are gas exchange and biotransformation (see later chapters). 

In competition, the C(6)-yl and C(5)-yl radicals may disproportionate, possibly via an adduct [reactions (80) and (81)]. This yields the hydrate via an enol [reaction (83)]. The other product is the glycol [reaction (82)]. In the original paper (Al-Sheikhly and von Sonntag 1983), it has been proposed that it maybe formed in an ET reaction. Due the considerable rearrangement energies involved in ET reactions as compared to radical recombination reactions, it is now considered that this ET reaction might occur via an addition/elimination process [reactions (80) and (81)] such as has also been found for other systems. 

A parallel study of aqueous bromination of pyrimidin-4(3//)-one and its /V-methyl derivatives also pointed to an addition-elimination process involving cationic intermediates. The kinetic results for these substrates differed from those of 39 (in which the pseudo bases dehydrate as neutral molecules) in that the intermediates dehydrated in cationic forms (79JOC3256). Again, the covalent hydrates, though present to only a minor extent (—0.0003%), were the reactive species in the bromination process. Pyrimidin-4(3//)-one, as its covalent hydrate, reacts 600 times faster than it does itself the rate enhancement is even greater O 104) for the 2-isomer, which exhibits a higher degree (—0.05%) of covalent hydration. 

We noted above that the charge distribution on the ring atoms of pyridine is not uniform, and the pattern is such that the 2- and the 4-positions are slightly electrophilic. If good leaving groups are attached to these sites, they may be readily displaced by nucleophiles in an addition-elimination process (Fig. 8-29). The displacement of halide from free 2- or 4-halopyridines is facile, and is the basis for the preparation of derivatives functionalised at these sites. In contrast, the 3-position is not activated towards nucleophilic attack and it is extremely difficult to derivatise pyridines at this site (Fig. 8-30). 

For R = C1, OMe besides SNH replacement at C-4, an addition-elimination process of the chloro atom or methoxy group by the... 

The addition-elimination mechanism for nucleophilic aromatic substitution requires strong electron-withdrawing substituents on the aromatic ring. Under extreme conditions, however, unactivated halobenzenes react with strong bases. For example, a commercial synthesis of phenol (the Dow process ) involves treatment of chlorobenzene with sodium hydroxide and a small amount of water in a pressurized reactor at 350 °C ... 

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