Nucleophilic substitution nucleofugal groups

Up to now, a few ways of fast conversion of a -adducts into products of S,.jArH were developed such as oxidation by external oxidants, conversion into substituted nitrosoarenes according to intramolecular redox stoichiometry, elimination of HL when nucleophiles contain nucleofugal groups L at the nucleophilic center, cine- and fefe-substitution, and addition of the nucleophile, ring opening, ring closure (ANRORC) process [1,2]. 

In nucleophilic substitution the attacking reagent (the nucleophile) brings an electron pair to the substrate, using this pair to form the new bond, and the leaving group (the nucleofuge) comes away with an electron pair ... 

The exceptional nucleofugality of the phenyliodonio group has been determined in an alkenyl salt and it is about 106 times greater than that of triflate [30]. This remarkable property makes alkenyl iodonium salts excellent vinyl cation equivalents in nucleophilic substitutions. The chemistry of alkenyl iodonium salts is dominated by the transfer of their aliphatic moiety to a variety of nucleophiles other important reactions involve Michael-type addition and alkylidenecarbene generation, along with elimination to alkynes which is actually an undesirable side-reaction. 

In the S l mechanism of aromatic substitution the initiating step is the formation of a radical anion. In order to distinguish the process from the route described above (SR+N1) in which a radical cation plays a crucial role, the symbol S l has been used17. Creation of the radical anion can occur by several procedures. The reaction can be electrochemically initiated, a solvated electron in a solution of alkali metal in liquid ammonia may be involved or a radical anion may be used as the source of electrons. The most common source of electrons is, however, the nucleophile itself involved in the substitution reaction. In many cases the electron transfer from nucleophile to substrate is light-catalysed and the process is then sometimes referred to as S l Ar. Although the nucleofugic group in S l... 

Finally, the global and local electrophilicity indexes may be also used to describe the nucleofugality of classical leaving groups in organic chemistry. This potential application incorporates the important families of nucleophilic substitution and elimination reactions. This study is however a bit more complex than the cases presented in this review, because the systematization of nucleofugality within an absolute scale requires an important number of requisites that must be fulfilled, most of them regarding the different reaction mechanisms involved in these complexe reactions. 

When a substituent with a good leaving ability is present in the 1,2,4-triazine ring at C-3, C-5, and/or C-6, nucleophilic substitution reactions can occur. Many SN reactions are described in the literature. In Sections IV,A-C, examples of displacement of one, two, and three nucleofugic groups are discussed. In this article, the displacement reactions are not exhaustingly reviewed. We show only the fundamental reaction features, their value, and scope for application in the synthesis of functionalized 1,2,4-triazine derivatives. As far as the mechanisms of nucleophilic sub-... 

Of all the nucleophilic substitutions in 1,2,4-triazines those which contain the two leaving groups at C-3 and C-5 have been studied most extensively. Triazines in which both C-3 and C-5 contain the same nucleofugic group have proved to be of particular interest. This is probably due to the fact that these starting materials are easily available. 

A rather complex mixture of products, i.e., 99, 100, 93, and 94, was obtained in the reaction of 3-methylthio-6-chloro-l,2,4-triazin-5-carboxa-mide (98) with ammonia (Scheme 60) (85JHC1329). It has been established that either of the nucleofugic groups in 98 are replaced by ammonia to form the 1,2,4-triazines 99 and 100 (Scheme 60). Substitution of the methylthio group at C-3 generates the nucleophilic methylthio anion, which causes a conversion of unreacted 98 into 3,6-dimethylthio-l,2,4-triazine 101. The latter undergoes subsequent reaction with ammonia to produce both isomeric SN products 93 and 94 (Scheme 60, see also Scheme 58). 

When the allyhc system carries X-substituents, and the solvent is polar, the reaction may take a unim-olecular path 4.162 > 4.164, and the reactions are then SN1 and SN1. The regioselectivity will be wholly determined by thermodynamic factors if the only available nucleophile is a good nucleofugal group, with the product 4.164 having the more-substituted double bond usually favoured. This selectivity will be enhanced by the greater steric hindrance usually present if the nucleophile is bonded to the more substituted site, and a corollary is that the thermodynamically less stable isomer 4.162 is the more reactive (by a factor of about 3 in ethanol at 25 °C in this case).395... 

Nucleophilic substitution occurs faster if there is a nucleofuge leaving group, e.g. ... 

Usually 4-fluoropyridines are synthesized from their nucleofuge-containing precursors by the nucleophilic substitution reaction. For example, 4-nitropyridines 90 react with TBAF in DMF with the formation of substituted 4-fluoropyridines 91 (Scheme 6.30). This reaction is highly regioselective despite the presence of relatively good leaving group (Cl or CN) in position 2 of pyridine. 

Amongst numerous practically important reactions belonging to this group there are nucleophilic substitution of nucleofugal groups in aliphatic and aromatic systems, addition of anions to electron-deficient C=0, C=N- and C=C bonds, oxidation, reduction, etc. 

The displacement of nucleofugal groups is usually realized through the addition-elimination two-step mechanism Sn(AE) . For instance, the trichloromethyl group in 1,2,4-triazines is displaced easily by the action of hydrazine, butylamine, sodium hydroxide, and alkoxides (Scheme 81) <2004SOS(17)357> however, in the reaction of 6-aryl-3-trichloromethyl-l,2,4-triazines with aromatic C-nucleophiles, substitution of hydrogen takes place <2004RCB1295>. 

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